Targeted approaches in the treatment of osteoporosis: differential mechanism of action of denosumab and clinical utility

Cavalli, Loredana; Brandi, Maria Luisa

doi:10.2147/tcrm.s7688

Cited by 12 publications

(11 citation statements)

References 102 publications

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“…Denosumab (Prolia®, Amgen Inc., Thousand Oaks, CA) is a fully human monoclonal antibody that binds with high affinity and specificity to RANK ligand and prevents the formation, function, and survival of osteoclasts [ 12 , 13 ]. In the pivotal F racture RE duction E valuation of D enosumab in O steoporosis every 6 M onths (FREEDOM) trial, denosumab reduced the incidence of vertebral, nonvertebral, and hip fractures over 3 years compared with placebo [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years

et al. 2015

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SummaryLimited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4–7 versus years 1–3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis.IntroductionThis study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates.MethodsParticipants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n = 2,343 long-term; n = 1,731 cross-over) who enrolled in the extension, missed ≤1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1–3 of denosumab with that of the fourth year and with the rate during years 4–7 was evaluated.ResultsFor the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR] = 0.64; 95 % confidence interval (CI) = 0.48 to 0.85, p = 0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1–3 were compared to years 4–7 in the long-term group (RR = 0.79; 95 % CI = 0.62 to 1.00, p = 0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD).ConclusionsDenosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.

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Section: Introductionmentioning

confidence: 99%

Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years

et al. 2015

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“… 17 Antiresorptive drugs generally act to reduce bone remodeling, and lower fracture risk by preserving the microarchitecture of the skeleton and increasing bone mass. 18 Antiresorptive drugs such as bisphosphonates are established therapies for PMO. 8 , 12 , 19 Denosumab is a relatively new antiresorptive agent that targets the cytokine system involved in bone turnover regulation (RANKL, a cytokine that is an essential mediator for osteoclast formation, function, and survival).…”

Section: Introductionmentioning

confidence: 99%

“…Anabolic treatments, such as teriparatide, have been used more recently to stimulate bone formation. 11 , 18 , 20 , 22 In addition, drugs such as strontium ranelate, which work by inhibiting the osteoclast and stimulating the osteoblast, have been approved for the treatment of PMO in Europe over the last few years. 20 , 23…”

Section: Introductionmentioning

confidence: 99%

Cost-utility of denosumab for the treatment of postmenopausal osteoporosis in Spain

Darbà¹,

Kaskens²,

Vilela³

et al. 2015

CEOR

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BackgroundThe objective of this study was to estimate the cost-effectiveness of denosumab for fracture prevention compared with no treatment, generic bisphosphonates, and strontium ranelate in a cohort of osteoporotic postmenopausal women in Spain.MethodsA Markov model represented the possible health state transitions of Spanish postmenopausal women from initiation of fracture prevention treatment until age 100 years or death. The perspective was that of the Spanish National Health System. Fracture efficacy data for denosumab were taken from a randomized controlled trial. Fracture efficacy data for alendronate, ibandronate, risedronate, and strontium ranelate were taken from an independent meta-analysis. Data on the incidence of fractures in Spain were either taken from the published literature or derived from Swedish data after applying a correction factor based on the reported incidence from each country. Resource use in each health state was obtained from the literature, or where no data had been published, conservative assumptions were made. Utility values for the various fracture health states were taken from published sources. The primary endpoints of the model were life-years gained, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios for denosumab against the comparators.ResultsDenosumab reduced the risk of fractures compared with either no treatment or the other active interventions, and produced the greatest gains in life-years and QALYs. With an annual acquisition cost of €417.34 for denosumab, the incremental cost-effectiveness ratios for denosumab versus no treatment, alendronate, risedronate, and ibandronate were estimated at €6,823, €16,294, €4,895, and €2,205 per QALY gained, respectively. Denosumab dominated strontium ranelate. Sensitivity analyses confirmed the robustness of these findings.ConclusionOur analyses show that denosumab is a cost-effective intervention for fracture prevention in osteoporotic postmenopausal women in Spain compared with alendronate and risedronate, and is a dominant treatment option compared with strontium ranelate.

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“…The simpler non-nitrogen-containing bisphosphonates (such as etidronate and clodronate, BPs of first generation) can be metabolically incorporated into nonhydrolysable analogues of adenosine triphosphate, which interfere with adenosine triphosphate-dependent intracellular pathways 86 . The more potent nitrogen-containing bisphosphonates (including pamidronate, alendronate, risedronate, ibandronate, and zoledronate) are not metabolized in this way but inhibit key enzymes of the mevalonate/cholesterol biosynthetic pathway, such as farnesyl pyrophosphate synthase, compromising the function of essential intracellular messengers, thus causing osteoclast inactivation and apoptosis 87 .…”

Section: Therapeutic Strategies For Enhancing Bone Mass Recovery Aftementioning

confidence: 99%

Periprosthetic bone loss: diagnostic and therapeutic approaches

Cavalli

Brandi

2014

F1000Res

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Total joint replacement surgery is being performed on an increasingly large part of the population. Clinical longevity of implants depends on their osseointegration, which is influenced by the load, the characteristics of the implant and the bone-implant interface, as well as by the quality and quantity of the surrounding bone. Aseptic loosening due to periprosthetic osteolysis is the most frequent known cause of implant failure. Wear of prosthetic materials results in the formation of numerous particles of debris that cause a complex biological response. Dual-energy X-ray Absorptiometry (DXA) is regarded as an accurate method to evaluate Bone Mineral Density (BMD) around hip or knee prostheses. Further data may be provided by a new device, the Bone Microarchitecture Analysis (BMA), which combines bone microarchitecture quantification and ultra high resolution osteo-articular imaging. Pharmacological strategies have been developed to prevent bone mass loss and to extend implant survival. Numerous trials with bisphosphonates show a protective effect on periprosthetic bone mass, up to 72 months after arthroplasty. Strontium ranelate has been demonstrated to increase the osseointegration of titanium implants in treated animals with improvement of bone microarchitecture and bone biomaterial properties.

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Targeted approaches in the treatment of osteoporosis: differential mechanism of action of denosumab and clinical utility

Cited by 12 publications

References 102 publications

Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years

Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years

Cost-utility of denosumab for the treatment of postmenopausal osteoporosis in Spain

Periprosthetic bone loss: diagnostic and therapeutic approaches

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