The mechanisms of action of bisphosphonates and denosumab with relation to the osteoclast. RANKL: receptor activator of nuclear factor kappa-B ligand
The second class of medication consists of the denosumab family. These antiresorptive drugs are fully human monoclonal antibodies against RANKL , which is a key cytokine in recruiting osteoclasts for bone resorption. Denosumab binds to and inhibits RANKL, which inhibits osteoclast maturation and activation [5, 6]. The biochemical structure does not lend itself to the skeletal retention seen with bisphosphonates, and thus the half-life is only several weeks with effects lasting several months [6, 7].
Bisphosphonates have been used initially to prevent the hypercalcemia of malignancy and have been quite effective in that function [8–15]. Most have been used extensively to prevent bone penetration and growth of malignancy by inhibiting the ability of the resident tumor to expand its foothold in the skeleton. A number of outstanding studies, including multiple meta-analyses, have consistently demonstrated that the bisphosphonates are effective in markedly decreasing skeletal events, complications of which are always a cause for concern when treating patients with metastatic bone disease. Various clinical trials have evaluated the efficacy of different bisphosphonates in the treatment of hypercalcemia of malignancy [8–15]. A meta-analysis of randomized clinical trials by Machado et al. found that clodronate, pamidronate, and zoledronate were associated with reductions in morbidity in cancer patients with metastatic bone disease . Phase III clinical trials of bisphosphonates have established their efficacy against bone complications in patients with breast cancer  while randomized control trials have shown skeletal-related event reductions with zoledronic acid in patients with breast cancer, prostate cancer, and multiple myeloma [10–12]. In addition, zoledronate was found superior in initial efficacy in a head-to-head comparison of pamidronate and zoledronate , which was performed in two randomized control trials . These bisphosphonates also have been shown to have some analgesic effect on metastatic bone pain . In a systemic review of the role of bisphosphonates on skeletal morbidity in bone metastasis, bisphosphonates were shown to significantly increase the time to first skeletal-related event suggesting that treatment with them should be initiated when bone metastases are diagnosed .
Denosumab similarly will lower hypercalcemia by inhibiting the osteoclast pathway. Its main action is to prevent the development of newly formed osteoclasts but it will not limit the activity of pre-existing osteoclasts. In most comparisons it appears to be more effective than bisphosphonates with the exception of multiple myeloma [16–22]. Denosumab does not bind to bone and requires constant dosing. Several studies have tested its efficacy. An evaluation of subjects undergoing denosumab treatment for 5 years found normal bone quality with reduced bone turnover, consistent with its mechanism of action, continued bone mineral density increases, and low fracture incidence . Treatment with denosumab has been proven to increase hip and spine strength as well as bone mineral density, volumetric bone mineral content, and density-weighted polar moment of inertia along the radius compared with both baseline and placebo, suggesting positive treatment effects in both the trabecular and cortical bone compartments [17, 18]. Direct comparisons of denosumab and bisphosphonates appear to favor denosumab. Denosumab was compared to zoledronate in two double-blind, randomized, controlled trials which showed either non-inferiority or superiority of denosumab to zoledronate with regard to skeletal-related events [19–21]. Lastly, even in situations of soft tissue involvement there appears to be some data to suggest that these agents may affect non-osseous metastases as well. In a randomized phase III study, denosumab was also more effective in delaying or preventing skeletal-related events in patients with bone metastasis from solid tumors and also prevented pain progression compared to zoledronate .
By lowering bone turnover, bisphosphonates and denosumab result in a loss of heterogeneity of the skeleton and accumulation of aged, non-replaced bone. Accumulation of microdamage has been established in older bone, but more recently studies have demonstrated that cancellous bone is susceptible to post-translational modifications of collagen, such as non-enzymatic glycation . This occurs through the presence of extracellular sugars and causes the formation of advanced glycation end-products (AGEs) . The accumulation of AGEs in bone leads to abnormal cross-linking of collagen resulting in an increase in its propensity to fracture . Several consequences have been noted clinically in the use of these agents. Most notably osteonecrosis of the jaw has occurred in the long-term use of bisphosphonates particularly accompanying simultaneous use of chemotherapy and immunosuppressive agents (e.g. corticosteroids) [24–27]. Bi et al. demonstrated that the development of necrotic bone and impaired soft tissue healing was dependent on long-term use of high-dose bisphosphonates, immunosuppressive and chemotherapy drugs, as well as mechanical trauma . It is highlighted by infections and bareness of the bone. Patients should improve their oral hygiene while oncologists and dentists should be aware of this complication and its management . There has been reported a slightly but significantly increased risk of osteonecrosis of the jaw with denosumab .
A second observation is the development of atypical femoral fractures . In these often transverse fractures, there is also a beak, evidence of a pre-existing stress fracture, which also manifests itself as a long prodromal period of pain before the fracture takes place (Fig. 12.2). Bilaterality is common and when that does occur usually it is in the exact same anatomic location (Fig. 12.3). This has been particularly the case with bisphosphonates and when dosed over a long period of time. A special notice is seen when associated with treatment of myeloma. Most recently, this has occurred in the setting of long-term survival of breast cancer patients using these agents.
Fifty-five year-old female patient diagnosed with metastatic breast cancer 6 years ago for which she had been on chronic zoledronic acid treatment. Patient presented to the office with insidious onset right thigh pain of 3 months’ duration (a). Note thickening of the lateral cortex (black arrow), a component of atypical femoral fractures . As pain was the presenting symptom, patient was diagnosed with impending atypical femoral fracture of the right femur and treated with prophylactic intramedullary nailing. (b) Zoledronic acid was also discontinued and teriparatide treatment initiated. Pathology report of canal reamings was negative for metastatic disease. (c) Eighteen months after fixation, stress reaction has remodeled considerably. Patient remained cancer-free during the treatment of her impending fracture
Seventy-four year-old female patient with a diagnosis of multiple myeloma on long-term (8 years) zoledronic acid therapy , presenting to the emergency department with subtrochanteric femoral fracture displaying atypical features incurred with minimal trauma (ground-level fall) (a). Note thickening of lateral cortex (large white arrow) and medial beaking (small white arrow), two major features of atypical femoral fractures. At the time of presentation, patient had no active myelomatous lesions. (b) Patient was treated emergently with long-stemmed hemiarthroplasty. Note lateral cortical thickening on the contralateral side (black arrow). Patient was asymptomatic on this side at this time. (c) Nine months after surgery, while under close follow-up for possible atypical fracture of the contralateral femur, patient developed symptoms of groin and thigh pain on this side. She was indicated for a total hip arthroplasty in the setting of primary osteoarthrosis of this hip. (d) At final follow-up, 10 years after initial surgery, patient’s stress reaction on the right side and fracture on the left have completely healed. Patient remains cancer-free
By the definition submitted by the Task Force of the American Society for Bone and Mineral Research, to be considered atypical, femoral fractures must demonstrate certain major features and may or may not display minor features (see Table 12.1) . Although atypical femoral fractures have initially been defined in osteoporotic patients on long-term bisphosphonate treatment with no evidence of malignancy, the common utilization of these agents as bone-protective drugs in metastatic cancer and these patients’ relative longevity with modern treatment may have left them vulnerable to this entity as well. Puhaindran et al. studied the incidence of atypical femoral fractures in a retrospective cohort of 327 patients with malignancy receiving bisphosphonate treatment and identified four patients (1.2 %), three with breast cancer and one with multiple myeloma, that sustained an atypical femoral fracture out of 14 femoral fractures altogether . Chang et al. reported six atypical fractures out of 62 femoral fractures in a mixed cohort of breast cancer and multiple myeloma patients and also demonstrated patients with atypical fractures received more intravenous bisphosphonates, zoledronic acid particularly, and were more likely to develop osteonecrosis of the jaw . Many independent case reports have also been published.
2010 American Society for bone and mineral research task force case definition of atypical femoral fractures 
• Located anywhere along the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare
• Associated with no trauma or minimal trauma, as in a fall from a standing height or less
• Transverse or short oblique configuration
• Complete fractures extend through both cortices and may be associated with a medial spike; incomplete fractures involve only the lateral cortex
• Localized periosteal reaction of the lateral cortexb
• Generalized increase in cortical thickness in the diaphysis
• Prodromal symptoms such as dull or aching pain in the groin or thigh
• Bilateral fractures and symptoms
• Delayed healing
• Comorbid conditions (e.g. vitamin D deficiency, RA, hypophosphatasia)
• Use of pharmaceutical agents (e.g. bisphosphonates, glucorticoids, proton pump inhibitors)
Specifically excluded are fractures of the femoral neck, intertrochanteric fractures with spiral subtrochanteric extension, pathologic fractures associated with primary or metastatic bone tumors, and periprosthetic fractures
Denosumab , which is a drug more recently developed, has been associated with the rare occurrence of these atypical fractures but often in the setting of prior long-term bisphosphonate therapy. Literature of atypical femoral fractures associated with denosumab therapy is as yet limited to case reports only [33–35].
As a consequence of these adverse events there is controversy as to how long the bisphosphonates and denosumab should be administered to cancer patients. Questions have arisen whether a loading form can take place, followed by a bone holiday akin to the method now utilized in osteoporosis. Denosumab does not bind irreversibly to bone and will undergo a recovery phase in which there is a hyper-metabolic state compared to the bisphosphonates. All may offer a lower risk for these adverse events. At the time of the writing of this chapter, the actual dosing process for both bisphosphonates and denosumab had not been established as an area of question.
The bisphosphonates appear to have some efficacy when used locally during surgical treatment of bony metastases as well. Bobyn et al. have demonstrated that porous prostheses that have had bisphosphonate surface treatment have improved bone ingrowth and a greater pull-out strength . The elution characteristics of locally delivered bisphosphonate have been described previously in the literature. Using this same delivery system in their 2005 paper, Tanzer et al. analyzed the amount of peri-implant bone formed around a cylindrical porous implant dosed with zoledronic acid and placed in the intramedullary canal of canine ulnae. Compared to the control group, bone in the zoledronic acid-dosed animals occupied 2.34-fold more space in the intramedullary canal, demonstrated greater than 58 % more ingrowth into the implant and individual bone islands, while of equivalent number, were 71 % larger . This improved ingrowth was found to be long-lasting as well, as reported by Bobyn et al. in 2009 . These authors also demonstrated that very small doses of zoledronic acid appear to be as effective . Similar improvements in bone ingrowth were demonstrated for alendronic acid-coated implants as well .
For implant choice during total hip arthroplasty in the metastatic setting, porous ingrowth prostheses have been rarely used and most orthopedic surgeons prefer cemented implants in this setting. Recent studies have demonstrated long stem prostheses with porous ingrowth appear to have the same clinical efficacy as the cemented prostheses without the pulmonary challenge caused by polymethymethacrylate (PMMA) ; therefore, bisphosphonates may have a role in these prostheses in the setting of metastatic disease. An alternative approach is to mix bisphosphonates into the PMMA, allowing the drug to migrate out of the cement to the adjacent bone and develop a shield to protect the bone from tumor growth. Healey and his co-workers have demonstrated that up to ten percent replacement with bisphosphonates does not alter the mechanical properties of the cement, which represents a potential method for supporting prostheses set in bone with large tumor burden . Randomized control studies testing out the efficacy of these agents are lacking at this time.
Another problem associated with the treatment of metastatic disease relates to osteolysis , which may cause loosening of prostheses independent of tumor. This could be troublesome particularly with long-term survivors. Patients who frequently receive chemotherapy become malnourished and this may result in a weakening of the bone-prosthesis attachment. In addition, some patients may develop cancer in the setting of an established diagnosis of osteoporosis while others develop osteoporosis secondary to the drug therapy they are receiving for it (i.e. steroids and chemotherapy). Samples of therapies that may in fact encourage osteoporosis are particularly related to multiple myeloma where steroids are often used and breast cancer where aromatase inhibitors have been developed to compromise the estrogen pathway . In the absence of estrogen, the skeleton will rapidly lose bone mass and osteoporosis has been documented with these agents [40–42]. Therefore, antiresorptive agents may play a role in preventing osteoporotic weakening of the skeleton and offsetting a potential fracture risk in terms of minor metastatic penetration. The osteoporosis doses for the bisphosphonates and denosumab are far lower than those used for the treatment of hypercalcemia associated with cancer and therefore may be safer. In fact there is no clear indication whether the cancer dose itself may represent over-treatment of osteoporosis.