RANK ligand inhibition with denosumab for the management of osteoporosis

Receptor activator of nuclear factor-κB ligand (RANKL) is a cytokine member of the tumour necrosis factor family that is the principal final mediator of osteoclastic bone resorption. It plays a major role in the pathogenesis of postmenopausal osteoporosis, as well bone loss associated with rheumatoid arthritis, metastatic cancer, multiple myeloma, aromatase inhibitor therapy and androgen deprivation therapy. Denosumab (AMG 162) is an investigational fully human monoclonal antibody with a high affinity and specificity for RANKL. By inhibiting the action of RANKL, denosumab reduces the differentiation, activity and survival of osteoclasts, thereby slowing the rate of bone resorption. Denosumab has been shown to increase bone mineral density (BMD) and reduce bone turnover in postmenopausal women with low BMD. Denosumab is a potential treatment for osteoporosis and other skeletal disorders.     

RANK ligand inhibition with denosumab for the management of osteoporosis

Receptor activator of nuclear factor-kappaB ligand (RANKL) is a cytokine member of the tumour necrosis factor family that is the principal final mediator of osteoclastic bone resorption. It plays a major role in the pathogenesis of postmenopausal osteoporosis, as well bone loss associated with rheumatoid arthritis, metastatic cancer, multiple myeloma, aromatase inhibitor therapy and androgen deprivation therapy. Denosumab (AMG 162) is an investigational fully human monoclonal antibody with a high affinity and specificity for RANKL. By inhibiting the action of RANKL, denosumab reduces the differentiation, activity and survival of osteoclasts, thereby slowing the rate of bone resorption. Denosumab has been shown to increase bone mineral density (BMD) and reduce bone turnover in postmenopausal women with low BMD. Denosumab is a potential treatment for osteoporosis and other skeletal disorders.     

Denosumab – an emerging treatment for postmenopausal osteoporosis

Importance of the field: Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling. Denosumab is an investigational fully human monoclonal antibody to receptor activator of NF-κB ligand (RANKL), a cytokine member of the TNF family that is the principal mediator of osteoclastic bone resorption.

Areas covered in this review: The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009.

What the reader will gain: This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis.

Take home message: In postmenopausal women with osteoporosis, denosumab (60 mg by subcutaneous injection every 6 months) increased bone mineral density, reduced bone turnover markers, and reduced the risk of vertebral, hip and non-vertebral fractures. Denosumab was well tolerated with a safety profile generally similar to placebo. It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis.     

Denosumab for the treatment of osteoporosis and cancer-related conditions

Osteoporotic fractures and adverse skeletal effects of malignancies are associated with high bone turnover. Denosumab is a potent inhibitor of bone resorption with a novel mechanism of action. It is administered as an infrequent subcutaneous injection with no restrictions relating to renal function. This review summarizes data on the efficacy and safety of denosumab that led to its approval for the treatment of postmenopausal osteoporosis, cancer treatment-induced bone loss, and skeletal complications of malignancies.     

Bisphosphonate therapy for postmenopausal osteoporosis.

Bisphosphonates are agents that are potentially useful for treatment of osteoporosis. They are antiresorptive agents, increasing bone mass by decreasing the frequency of osteoclast activation or the depth of osteoclast resorption, or both. Intermittent cyclical therapy with etidronate has been shown to be effective for postmenopausal osteoporosis in two controlled studies. Several second- and third- generation bisphosphonates are undergoing active clinical trials.     

Teriparatide (rhPTH 1-34) for the treatment of osteoporosis

Osteoporosis is a skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture. Osteoporosis develops through an imbalance between bone resorption by osteoclasts and bone formation by osteoblasts resulting in increased bone loss. Numerous agents used for the prevention and treatment of osteoporosis slow bone loss by decreasing both bone resorption and formation. These include bisphosphonates, hormone replacement therapy, selective oestrogen receptor modulators and calcitonins. All reduce vertebral fracture risk and some reduce non-vertebral fracture risk, but none routinely increases bone mass and strength or restores lost bone architecture. In many respects, antiresorptive therapies halt the progression of osteoporosis. However, for patients who have osteoporosis, particularly those who have sustained their first fracture and are at high risk for subsequent fractures, there is a need to develop agents that stimulate bone formation and, thus, reverse osteoporosis. Teriparatide is the recombinant human 1-34 amino acid sequence of parathyroid hormone recently approved in the US for the treatment of men and postmenopausal women at high risk for osteoporotic fracture and in Europe for the treatment of postmenopausal women with osteoporosis. When given by once-daily injection, teriparatide increases bone mass by stimulating formation of new bone, resulting in the restoration of bone architecture.     

Denosumab for the management of postmenopausal osteoporosis

View the National Osteoporosis Foundation Clinician's Guide Postmenopausal osteoporosis is a major concern to public health. Fractures are the major clinical consequence of osteoporosis and are associated with substantial morbidity, mortality, and health care costs. Despite the availability of screening and treatment guidelines, osteoporosis diagnosis and treatment remain low. Health care providers may consult guidelines in the clinical management of their patients with osteoporosis, including those from the National Osteoporosis Foundation, and the new fracture risk assessment tool from the World Health Organization. Bisphosphonates are the most commonly used treatment for postmenopausal osteoporosis. Although these agents are effective in preventing fractures and bone loss, the benefits of treatment may be limited by suboptimal adherence and compliance. Denosumab is a human monoclonal antibody that targets and inhibits RANK ligand, an essential mediator of bone resorption. In clinical trials in postmenopausal women with osteoporosis, denosumab 60 mg given subcutaneously every 6 months was well tolerated and statistically significantly reduced the risk of vertebral, nonvertebral, and hip fractures. The introduction of denosumab into clinical practice provides physicians with another option for the treatment of postmenopausal osteoporosis, and the twice-yearly dosing regimen has the potential to improve adherence.     

Update of current therapeutic options for the treatment of postmenopausal osteoporosis

BACKGROUND: Osteoporosis is a common chronic condition in elderly women and is associated with decreased bone strength and an increased risk for fractures. As the incidence of osteoporotic fractures continues to rise, it is important to identify the most effective therapies for reducing patients' risk of fracture. OBJECTIVE: This article reviews the medication classes commonly used for treating osteoporosis and the efficacy, tolerability, and drug-interaction potential of specific medications. The evidence for the use of combination therapies is summarized, as are the agents under investigation. METHODS: Relevant articles were identified through a search of MEDLINE (August 1985-August 2005) using the terms osteoporosis, postmenopausal, fracture, and efficacy combined with drug therapy, calcium, vitamin D, estrogen, progesterone, selective estrogen modulators, calcitonin, strontium ranelate, bisphosphonates, alendronate, risedronate, ibandronate, pamidronate, parathyroid hormone, combination therapy, and zoledronic acid. The identified articles were reviewed for suitability, with priority given to meta-analyses. RESULTS: Among the therapeutic options for the treatment of osteoporosis, the bisphosphonates appear to provide the greatest antiresorptive efficacy, with some bisphosphonates providing 7% to 8% increases in bone mineral density and 60% to 70% decreases in markers of bone resorption. Bisphosphonates also may reduce the incidence of new vertebral fractures by 50% to 52%. CONCLUSIONS: Bisphosphonates are currently the first choice for the treatment of osteoporosis. Use of intermittent regimens of the newer bisphosphonates appears to be a promising alternative to administration of daily or weekly treatment.     

Circulating levels of osteoclast activating cytokines, interleukin-11 and transforming growth factor-beta2, as valuable biomarkers for the assessment of bone turnover in postmenopausal osteoporosis

The objective of this study was to evaluate the role of osteoclast activating cytokines, interleukin-11 (IL-11) and transforming growth factor-beta2 (TGF-beta2) in the assessment of bone turnover in postmenopausal osteoporosis (PO). Eighty postmenopausal osteoporotic women with lumbar spine bone mineral densities (BMD) as measured by DEXA that were more than 2.5 SD below the normal mean of healthy women (controls), participated in this study. Various therapeutic modalities (hormone replacement therapy, HRT, alendronate, calcitonin and 1alpha-hydroxyvitamin D (alfacalcidol) were administered for 12 months to 4 groups of postmenopausal osteoporotic patients. Fasting blood samples and two hour urine samples were collected from control subjects and from patients before and after treatment. Serum samples were assayed for IL-11, TGF-beta2, osteocalcin (OC) and bone alkaline phosphatase (B-ALP), whereas urine samples were assayed for N-telopeptide for type I collagen (NTX) and deoxypyridinoline (DPyr). The results demonstrated a significant increase of both IL-11 and TGF-beta2 in postmenopausal osteoporosis. Positive correlations exist between TGF-beta2 or IL-11 and markers of bone resorption (NTX and DPyr). Moreover, there was a significant positive correlation between TGF-beta2 and IL-11. Therapeutic modalities enhancing bone formation and/or with antiresorptive effect revealed a significant decrease in markers of bone resorption, formation and osteoclast activating cytokines, indicating a decrease in bone turnover. The decrease of IL-11 and TGF-beta2 may be attributed to a drug inhibitory effect of these cytokines on enhancing osteoblast mediated osteoid degradation. In conclusion, both serum IL-11 and TGF-beta2 determinations may be considered as biomarkers for the assessment of bone turnover and for monitoring antiresorptive therapy in postmenopausal osteoporosis.     

Denosumab for treatment of breast cancer bone metastases and beyond

INTRODUCTION: Bone metastases develop in approximately 70 - 85% of patients with metastatic breast cancer, are incurable and can result in debilitating skeletal complications. Bone-modifying agents to treat breast cancer bone metastases include bisphosphonates. Denosumab is a humanized monoclonal IgG2 antibody targeting receptor activator of NF-κB ligand (RANKL) and provides an alternative therapy for treatment of breast cancer bone metastases. AREAS COVERED: This review provides an overview on denosumab and the RANKL-RANK pathway. Denosumab pharmacokinetics, pharmacodynamics, efficacy, safety and tolerability are discussed. Based on the review of clinical studies, denosumab is efficacious in the treatment of breast cancer bone metastases. Adverse events rates of denosumab are similar to those for bisphosphonates. Preclinical studies have indicated a role of the RANKL-RANK pathway in non-bone-related mechanisms such as mammary gland development and tumorigenesis. EXPERT OPINION: Clinical use of denosumab remains limited and its place in therapy will continue to be defined. Clinical questions, such as the optimal duration of therapy, remain unanswered and need to be addressed.     

Denosumab for treatment of breast cancer bone metastases and beyond

Introduction: Bone metastases develop in approximately 70 – 85% of patients with metastatic breast cancer, are incurable and can result in debilitating skeletal complications. Bone-modifying agents to treat breast cancer bone metastases include bisphosphonates. Denosumab is a humanized monoclonal IgG2 antibody targeting receptor activator of NF-κB ligand (RANKL) and provides an alternative therapy for treatment of breast cancer bone metastases.

Areas covered: This review provides an overview on denosumab and the RANKL–RANK pathway. Denosumab pharmacokinetics, pharmacodynamics, efficacy, safety and tolerability are discussed. Based on the review of clinical studies, denosumab is efficacious in the treatment of breast cancer bone metastases. Adverse events rates of denosumab are similar to those for bisphosphonates. Preclinical studies have indicated a role of the RANKL–RANK pathway in non-bone-related mechanisms such as mammary gland development and tumorigenesis.

Expert opinion: Clinical use of denosumab remains limited and its place in therapy will continue to be defined. Clinical questions, such as the optimal duration of therapy, remain unanswered and need to be addressed.     

Osteoprotegerin serum levels in women: correlation with age,bone mass,bone turnover and fracture status

Pre-clinical data have shown that osteoprotegerin (OPG) inhibits osteoclast function and therefore plays an important role in bone remodelling. This study aimed to evaluate the clinical value of serum OPG. Do higher OPG serum levels reflect decreased bone resorption and perhaps higher bone mass in women? Serum OPG levels were measured in 177 healthy women (aged 17-85 years) and in 48 untreated patients (mean age 71 +/- 5) with established osteoporosis, and related to age, bone mass, markers of bone turnover and, in the case of patients with osteoporosis, to pre-existing vertebral fractures. In healthy women OPG levels showed a positive correlation with age (r = 0.25, p < 0.001) but not to bone mass or markers of bone turnover. In women with osteoporosis, however, there was a strong relationship between serum OPG and markers of bone turnover (serum c-terminal crosslinked telopeptides of thpe I collagen (sCTX): r = +0.82, p < 0.0001; osteocalcin (OC): r = +0.69, p < 0.0001), with patients who had higher levels of bone-turnover markers showing higher serum levels of OPG. After adjustment for bone mass and bone markers, patients with pre-existing vertebral fractures had significantly lower serum OPG levels than patients without fractures (57 +/- 8 vs. 97 +/- 10 pg/ml, [mean +/- SE], p < 0.01). The age-dependent increase of OPG as an antiresorptive factor may reflect an insufficient paracrine mechanism of bone cells to compensate for bone loss in older age. In patients with osteoporosis, however, OPG correlated strongly with markers of bone turnover; this may point toward a higher level of RANKL/OPG expression in these patients. Finally, low OPG serum levels seem to be associated with vertebral fractures. We hypothesise that low OPG levels in preset conditions of bone turnover may indicate a higher risk of fracture in patients with osteoporosis.     

Role of denosumab in breast cancer

Recent advances in adjuvant treatment have improved progression-free and overall survival in patients with early stage breast cancer. However, up to one third of women will experience tumour recurrence, with bone being a common metastatic site. Current treatment options for metastases to bone comprise systemic antitumour therapy, irradiation, surgery and biphosphonates. As osteoclast activation is mediated by the receptor activator of NF-κB (RANK)/RANK ligand pathway and inhibited by osteoprotegerin (OPG), it was suggested that inhibition of this system may treat bone metastases. Recombinant Fc-OPG was evaluated in women with osteoporosis and malignant bone disease. The fully human antibody denosumab has demonstrated superior activity in reducing markers of bone turnover; therefore this drug was further developed in clinical settings. In advanced breast cancer, denosumab reduced urinary-N-telopeptide:creatinine ratio with potentially fewer side effects compared with bisphosphonates. Proof of direct antitumor activity is missing. Here we review the development and current status of denosumab in breast cancer. Data were obtained by searching the Medline database and abstracts from the American Society for Clinical Oncology (ASCO) annual meeting, European Cancer organization (ECCO), European Society for Medical Oncology (ESMO) and the San Antonio Breast Cancer Symposium, using search terms including bone metastases, bisphosphonates, breast cancer, denosumab, osteoprotegerin, RANK and skeletal-related events.     

Monoclonal antibodies for treating osteoporosis

Introduction: Osteoporosis is the most widespread skeletal disease requiring innovative therapeutic strategies for its management. The understanding of receptor activator of nuclear factor kappa-B ligand (RANKL) and sclerostin’s role in bone cell biology is completely changing the therapeutic landscape. RANKL supports osteoclast formation and activity and is mainly produced by cells of osteoblastic lineage. Sclerostin, an antagonist of the Wnt pathway, has a key role in bone formation and is mainly secreted by osteocytes. High levels of RANKL and sclerostin have been detected in osteoporosis, leading to the production of antibodies able to neutralize their activity.

Areas covered: In this review, the authors give an overview and discuss the literature and data on denosumab and romosozumab to treat osteoporosis. Clinical studies indicate that long-term treatment with denosumab causes a continuous increase in bone mineral density with low incidence of adverse effects. Romosozumab treatment gives increases bone formation and improves bone mineral density (BMD) though further studies are needed to better evaluate the adverse effects.

Expert opinion: Denosumab and romosozumab show promise in the treatment of osteoporosis. Furthermore, their different mechanisms of action compared to existing anti-osteoporotic drugs may permit alternative strategies for osteoporosis treatment down the line.     

Comparing therapies for postmenopausal osteoporosis prevention and treatment

OBJECTIVE: To review the literature concerning the efficacy of calcium, hormone replacement therapy (HRT), bisphosphonates, selective estrogen receptor modulators, and calcitonin in the prevention and treatment of postmenopausal osteoporosis. DATA SOURCES: Articles were identified through searches of the MEDLINE (1966-July 2002), EMBASE (1980-July 2002), and International Pharmaceutical Abstracts (1970-July 2002) databases using the key words osteoporosis, postmenopausal, fracture, calcium, vitamin D, hormone replacement therapy, bisphosphonates, alendronate, risedronate, raloxifene, and calcitonin. Additional references were located through review of the bibliographies of the articles cited. Searches were not limited by time restriction, language, or human subject. STUDY SELECTION AND DATA EXTRACTION: Experimental and observational studies of the use of calcium and antiresorptive therapies for the prevention and treatment of postmenopausal osteoporosis were selected. Articles evaluating bone mineral density (BMD) or fracture efficacy were included in this review. DATA SYNTHESIS: HRT, bisphosphonates, raloxifene, and calcitonin have demonstrated stabilization of and improvement in BMD. Randomized clinical trials have shown fracture risk reduction with bisphosphonates, raloxifene, HRT, calcium, and calcitonin. The largest risk reductions have been reported with use of bisphosphonates in several trials. CONCLUSIONS: Several therapeutic options with well-documented improvements in BMD and reductions in fracture risk are available to women for the prevention and treatment of postmenopausal osteoporosis.     

RANKL inhibition: Clinical implications for the management of patients with multiple myeloma and solid tumors with bone metastases

Background: Receptor activator of NF-κB ligand (RANKL) binds to RANK on the surface of osteoclast precursors and enhances their differentiation, survival and fusion, activates mature osteoclasts and inhibits their apoptosis. Osteoprotegerin (OPG) is the decoy receptor of RANKL. Disruption of the RANK/RANKL/OPG axis is implicated in bone metastases. Objective/methods: A review of the role of RANKL signaling in bone development and the rationale for targeting RANKL in treatment of bone metastases and myeloma bone disease. Results/conclusions: In preclinical models of solid tumors and myeloma, RANKL inhibition reduced osteoclast numbers and subsequent bone resorption, prevented development of osteolytic lesions and decreased tumor burden. Preliminary clinical studies with denosumab, an anti-RANKL fully human monoclonal antibody, in patients with solid tumors with bone metastases and myeloma showed that targeting RANKL reduces osteoclastogenesis, bone resorption markers and skeletal-related events, supporting further study of this molecule and others with anti-RANKL activity.     

Osteoporosis related to disease or therapy in patients with cancer

Osteoporosis is a major public health issue in the general population, particularly in postmenopausal women. Patients with cancer may not only be at risk for primary osteoporosis, but for secondary osteoporosis related to cancer therapies-particularly therapies that impair gonadal function, lead to loss of serum estrogen, and negatively affect bone turnover. Normal bone remodeling is influenced by the receptor activator for nuclear kappa-B ligand pathway, calcium, vitamin D, and other nutrition factors, as well as modifiable and nonmodifiable factors. Identifying which patients with cancer are at risk for bone mineral density loss is important and may include patients with breast or prostate cancer, some survivors of pediatric malignancies, and adults with other tumors. Nurses play a major role in identifying those patients and their risk for low-impact fractures, which can have a significant effect on patient morbidity and mortality. Counseling and teaching are central nursing functions, as well as safely administering therapies, particularly bisphosphonates and denosumab.     

IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation

T cell-produced cytokines play a pivotal role in the bone loss caused by inflammation, infection, and estrogen deficiency. IFN-gamma is a major product of activated T helper cells that can function as a pro- or antiresorptive cytokine, but the reason why IFN-gamma has variable effects in bone is unknown. Here we show that IFN-gamma blunts osteoclast formation through direct targeting of osteoclast precursors but indirectly stimulates osteoclast formation and promotes bone resorption by stimulating antigen-dependent T cell activation and T cell secretion of the osteoclastogenic factors RANKL and TNF-alpha. Analysis of the in vivo effects of IFN-gamma in 3 mouse models of bone loss - ovariectomy, LPS injection, and inflammation via silencing of TGF-beta signaling in T cells - reveals that the net effect of IFN-gamma in these conditions is that of stimulating bone resorption and bone loss. In summary, IFN-gamma has both direct anti-osteoclastogenic and indirect pro-osteoclastogenic properties in vivo. Under conditions of estrogen deficiency, infection, and inflammation, the net balance of these 2 opposing forces is biased toward bone resorption. Inhibition of IFN-gamma signaling may thus represent a novel strategy to simultaneously reduce inflammation and bone loss in common forms of osteoporosis.     

Etidronate

Intermittent cyclical therapy with etidronate increases bone mineral density in spine and hip, and reduces the incidence of new vertebral fractures in women with postmenopausal osteoporosis, as well as steroid-induced osteoporosis. Seven years treatment with etidronate was reported to be safe, effective and well-tolerated. And additive effects of etidronate were documented in bone mineral density when hormone replacement therapy was combined. Recently many bisphosphonates have been commercially available in clinics. Although the potency of etidronate to inhibit bone resorption is relatively weak among those bisphosphonates, equal effects for others in osteoporosis can be obtained with the intermittent therapy, which is easy to be complied for the patients with less adverse events. In conclusion cyclical etidronate therapy is still important for osteoporosis therapy.     

Pharmacologic and nonpharmacologic management of osteoporosis

Fractures that occur as a result of osteoporosis are associated with significant morbidity, mortality, and cost. A treatment regimen consisting of both nonpharmacologic and pharmacologic interventions can be used to decrease the risk of fracture. Nonpharmacologic interventions include calcium and vitamin D supplementation, weight-bearing exercise, muscle strengthening, and fall prevention. Pharmacologic options include: the bisphosphonates, estrogen therapy, raloxifene, salmon calcitonin, and the anabolic agent teriparatide. Although bone mineral density is used clinically to diagnose osteoporosis, it is of limited value when evaluating pharmacologic treatment; the primary indicator of treatment efficacy is fracture risk reduction. The bisphosphonates are the preferred therapy for osteoporosis. Studies have demonstrated that in postmenopausal women, both risedronate and alendronate are associated with reductions in vertebral and nonvertebral fracture risk. The newest approved bisphosphonate, ibandronate, reduces vertebral fracture risk. Studies also support a reduction in fracture risk when alendronate and risedronate are used in men with osteoporosis and patients with corticosteroid-induced osteoporosis. When used appropriately, the bisphosphonates are well tolerated. Estrogen and raloxifene decrease fracture risk in postmenopausal women with osteoporosis but are associated with thromboembolic events. Use of estrogen therapy is also limited by concerns about the safety of this type of therapy. Although the anabolic agent teriparatide is associated with reductions in vertebral and nonvertebral fractures, its use has been limited by the necessity of subcutaneous administration and its cost relative to other agents. Regardless of which treatment regimen is selected, health care providers need to emphasize the importance of compliance and adherence to improve persistence with therapy, and subsequent fracture reduction efficacy.