© Borgis - Postępy Nauk Medycznych 1/2017, s. 37-42
*Michał Wąsowski, Magdalena Proniewska-Sadowska, Urszula Budzińska
Bisphosphonates and denosumab – the efficacy in the fracture prevention
Bisfosfoniany i denosumab – skuteczność w zapobieganiu złamaniom
Department of Geriatrics, Internal Medicine and Metabolic Bone Diseases, Centre of Postgraduate Medical Education, Warsaw
Head of Department: Associate Professor Marek Tałałaj, MD, PhD
W oczekiwanym okresie życia 1 na 2 kobiety po menopauzie i 1 na 5 mężczyzn w starszym wieku są narażeni na wystąpienie złamania w przebiegu osteoporozy. Złamania osteoporotyczne są najgroźniejszymi powikłaniami osteoporozy, zwłaszcza zlokalizowane w bliższej części kości udowej. Osteoporoza i wikłające ją złamania związane są ze zwiększoną chorobowością i śmiertelnością. Celem leczenia jest zmniejszenie tempa utraty kości, zwiększenie jej wytrzymałości oraz redukcja ryzyka złamań niskoenergetycznych. Bisfosfoniany (BPs) łącznie z suplementacją wapnia i witaminą D przez wiele lat stanowiły podstawową terapię w prewencji i leczeniu złamań ostoporotycznych. Silnie i wybiórczo wiążą się one z tkanką kostną hamując aktywność komórek kościogubnych – osteoklastów. Denosumab jest ludzkim przeciwciałem monoklonalnym wiążącym ligand receptora jądrowego czynnika kappaB (RANKL) wytwarzanym przez osteoblasty, komórki szpiku kostnego oraz limfocyty T. Zmniejszona stymulacja receptora RANK, obecnego na dojrzałych osteoklastach i ich prekursorach, powoduje zarówno zahamowanie migracji, różnicowania oraz fuzji prekursorowych komórek hemopoetycznych linii osteoklastycznej, jak i aktywności oraz przeżycia dojrzałych osteoklastów. Udokumentowano, że bisfosfoniany i denosumab są skuteczne w prewencji złamań u pacjentów z osteoporozą i/lub przebytymi złamaniami kręgów, zmniejszając ryzyko złamań kręgosłupa o więcej niż 50%, ryzyko złamań pozakręgowych o 20-25% i złamań biodra o 40-50%. Wybór rodzaju terapii u pacjentów z osteoporozą powinien uwzględniać nie tylko jej skuteczność i bezpieczeństwo, ale także wpływ na systematyczność jej stosowania.
During one’s expected remaining lifetime, 1 in 2 postmenopausal women and 1 in 5 older men are at risk for an osteoporosis-related fracture. Osteoporotic fractures are the most devastating complications of osteoporosis, especially those of the hip. The osteoporosis and the consequent fractures are associated with increased morbidity and mortality. The aim of the therapy is to diminish the rate of bone loss, to increase bone strength, and to reduce the risk of low energy fractures. Bisphosphonates (BPs), together with calcium and vitamin D supplementation, have been considered for many years, as a first line therapy for the prevention and treatment of osteoporosis. They are able to bind strongly and selectively to bone mineral and to inhibit the activity of bone resorbing cells – osteoclasts. Denosumab is a fully human monoclonal antibody that can bind receptor activator of nuclear factor kappaB ligand (RANKL) secreted by osteoblasts, bone marrow stromal cells, and T cells. Reduced stimulation of RANK receptors, presented on mature osteoclasts and their precursors, results in inhibition of migration, differentiation, and fusion of hematopoietic cells of the osteoclast lineage as well as in decreased activity and survival of mature osteoclasts. It was documented that bisphosphonates and denosumab are effective in fracture prevention among patients with osteoporosis and/or prevalent vertebral fracture, decreasing the incidence of vertebral fractures by more than 50%, non-vertebral fractures by 20-25% and hip fractures by 40-50%. The choice of the treatment among osteoporotic patients should consider not only their effectiveness and safety but also such important factors as compliance and adherence to the drug.
Low energy fractures are the most devastating complications of osteoporosis. They occur most often at the hip, spine and forearm but may occur throughout the whole skeleton. Osteoporotic fractures especially those of the hip and spine appear most often in elderly people and are associated with increased morbidity and mortality (1, 2).
The main goal of treatment of osteoporosis is to prevent low energy fractures or at least significantly reduce the risk of their incidence. Current osteoporosis therapies have been developed to decrease bone resorption and/or to increase bone formation. Most often used medications are powerful inhibitors of bone resorption: bisphosphonates and denosumab (3).
BISPHOSPHONATES AND DENOSUMAB – DIFFERENT MOLECULES, DIFFERENT ACTIONS
Bisphosphonates (BPs), together with calcium and vitamin D supplementation, have been considered for many years, as a first line therapy for the prevention and treatment of osteoporosis. BPs are able to bind strongly and selectively to bone mineral and to inhibit the activity of bone resorbing cells – osteoclasts. BPs influence mainly trabecular bone turnover, because they are primarily located across bone surfaces, especially those with adjacent bone marrow, such as endocortical and trabecular surfaces.
Bisphosphonates have to be internalized to act upon osteoclasts (4, 5). BPs suppress the birth of new remodeling units, with fewer and shallower resorption cavities, and maintain bone structure with more complete mineralization. Nitrogen-containing BPs, such as alendronate, risedronate, ibandronate and zoledronic acid, cause long-term inhibition of the mevalonate pathway in osteoclasts, and accelerate their apoptosis (6).
Based on the results of randomized controlled trials (RCTs) all nitrogen containing BPs have been accepted for the prevention and treatment of postmenopausal osteoporosis. Alendronate, risedronate and zoledronic acid were also accepted for osteoporosis in men as well as for prevention and treatment of glucocorticoid-induced osteoporosis.
RCTs are performed for daily oral formulations of the drugs. The other formulations, once weekly or monthly, were granted on the basis of bone mineral density bridging studies and pharmacokinetic measurements.
All BPs are contraindicated in patients with hypocalcemia. Oral formulations should be avoided in patients with abnormalities of the esophagus which delay its emptying, and used with caution in persons with upper gastrointestinal diseases and in individuals unabled to stand or sit upright for at least 30 minutes. The drugs are not recommended in patients with renal impairment with glomerular filtration rate (GFR) < 30-35 ml/min (7).
Side-effects include upper gastrointestinal symptoms, bowel disturbances, headaches and musculoskeletal pains, while intravenous administration may be associated with an acute phase reaction, characterized by an influenza-like illness, which is generally short-term and typically occurs mainly after the first injection.
The intestinal absorption of BPs is extremely poor (between 1 and 3%) and bioavailability of the drugs can vary considerably. Absorption of the oral BPs occurs rapidly, with maximum serum concentrations reached in 30-60 minutes but is substantially reduced and delayed if the drugs are taken with meals, especially rich in calcium.
Virtually the whole absorbed dose is either taken up into bone tissue or eliminated with urine. BPs have a high affinity for exposed hydroxyapatite surfaces ready for or undergoing bone resorption and they are selectively bound with mineralized bone tissue. It was found that approximately 50-60% of the absorbed oral dose of risedronate and alendronate is taken up by the bones. Following the administration of a 10 mg dose of intravenous radiolabeled alendronate the serum concentration of the drug declined by over 95% within 6 hours and was undetectable after 15 hours. Risedronate was found to be eliminated from the circulation with serum half-life of 1.5 hours (8).
The first generation bisphosphonates such as etidronate and clodronate decrease bone resorption by reversing pyrophosphorylytic reactions catalyzed by aminoacyl-tRNA synthetases. The activity of the nitrogenated BPs seems to result mainly from their capacity of inhibiting farnesyl pyrophosphate synthase (FPPS) activity in the mevalonate pathway. The bisphosphonate concentration to inhibit 50% of enzyme activity was found to be 500 nM for pamidronate, 460 nM for alendronate, and 3.9 nM for risedronate. It was documented that the potency for inhibiting human FPP synthase in vitro was highly correlated with antiresorptive potency in vivo. The order of potency at inhibiting the enzyme: zoledronic acid > risedronate > ibandronate > alendronate > pamidronate matched closely the order of antiresorptive potency of BPs, suggesting that FPP synthase is a major pharmacologic target for BPs (8).
Strong affinity for bone tissue provides bisphosphonates with the capacity of remaining embedded in bone matrix for a long time, thus making possible weekly, monthly or even yearly regimens (8).
BPs remain sequestered in bone tissue for extended time, then they are gradually released to the circulation depending on the rate of bone turnover. In healthy human volunteers, the plasma terminal elimination half-life following a single oral dose of 30 mg risedronate was 224 hours, and increased to 480 hours following multiple doses of the drug. The terminal half-life of zoledronic acid was found to be 146 hours and of ibandronate was estimated for 10-60 hours (8).
Inhibition of bone resorption by BPs was dependent on the dose and dosing interval with intermittent administration. In patients treated with BPs bone resorption was found not to become progressively lower but reached a new steady level, suggesting that, despite accumulation of BPs in the skeleton, bone turnover still continues, thought at a slower rate (9).
Denosumab is a fully human monoclonal antibody that can bind receptor activator of nuclear factor kappaB ligand (RANKL) secreted by osteoblasts, bone marrow stromal cells, and T cells (10, 11). Reduced stimulation of RANK receptors, present on mature osteoclasts and their precursors, results in inhibition of migration, differentiation, and fusion of hematopoietic cells of the osteoclast lineage as well as in decreased activity and survival of mature osteoclasts (12).
Denosumab is administered subcutaneously every 6 months. Following the infusion the drug circulates in the blood and extracellular fluid reaching both trabecular and cortical bone tissue including intracortical sites (3). Therapy with denosumab results in significant inhibition of bone resorption and bone turnover that resolves within 1 year after stopping treatment (4, 5, 13).
BISPHOSPHONATES IN FRACTURE PREVENTION
All BPs accepted for the prevention and treatment of osteoporosis were found to reduce significantly the incidence of skeletal fractures.
Alendronate, given orally at the dose of 10 mg daily or 70 mg once weekly, was proved to reduce the risk of vertebral, non-vertebral and hip fractures in postmenopausal women with osteoporosis (7).
Risedronate, given orally at a dose of 5 mg daily or 35 mg once weekly, was shown to reduce the incidence of both vertebral and non-vertebral fractures, and in elderly women with low bone mineral density (T-score < -2.5) to decrease the risk of hip fractures as well (14, 15).
Ibandronate is the only BP that can be given orally at the doses of 2.5 mg daily or 150 mg once monthly or as an intravenous injection given every 3 months at a dose of 3 mg. In women treated with the drug at a dose of 2.5 mg daily significant reduction in a vertebral fracture rate was demonstrated, while in a post hoc analysis of high risk women with extremely low bone mineral density (BMD) – femoral neck T-score < -3.0 – a significant reduction in non-vertebral fractures was shown as well (16, 17).
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