ARTIGO DE REvISÃO

Denosumab: recent update in postmenopausal

Inês Silva 1, Jaime C Branco 1,2

ACTA REUMATOL PORT. 2012;37:302-313

AbstrAct strength and increased risk of fractures 2. Is a worldwi - de public health problem with serious consequences Postmenopausal osteoporosis is a major concern to pu - in personal suffering and economical costs 3,4 . Clinical blic health. Fractures are the major clinical consequen - tools to diagnose OP and predict fracture risk are avai - ce of osteoporosis and are associated with substantial lable but patients who are at risk for fracture or with a mor bidity, mortality and health care costs. previous fracture are very often not identified or trea - strength determinants such as bone mineral density ted 3,5-8 . The unit (BRU) includes a se - and bone quality parameters are determined by life- quence of events, during which (OC) resorb long remodeling of skeletal tissue. Receptor activator of bone over a period of 3 weeks, creating cavities that are nuclear factor-kB ligand (RANKL) is a cytokine essen - termed as remodeling space. The resorption is follo - tial for differentiation, activation and survi - wed by (OB) activation and osteoid forma - val. Denosumab (Prolia®) is a fully monoclo - tion, filling the cavities over a period of 3 months. nal antibody for RANKL, which selectively inhibits os - When the matrix synthesis is finished OB become em - teoclastogenesis, being recently approved for the treat - bedded in the matrix as (that will function ment of postmenopausal osteoporosis in women at a as mechanoreceptors) 3,9 . Bone remodeling permits the high or increased risk of fracture by the FDA in the Uni - repair of microdamage, maintains normal skeletal mass ted Sates and by the European Medicines Agency in Eu - and participates in regulation of systemic ho - rope since June 2010. FREEDOM, DECIDE and meostasis 9,10-13 . As /formation is tightly STAND are the phase 3 trials comparing denosumab coupled, inhibition of resorption eventually results in with placebo and alendronate in postmenopausal os - inhibition of formation 9 (Figure 1). OP therapy may be teoporosis. The authors aim to update denosumab role classified as antiresorptive (estrogens, , in postmenopausal osteoporosis with a physiopatholo - and raloxifene) or anabolic [ (re - gical review. combinant human parathyroid hormone PTH1-34) or PTH1-84)]. appears to have both Keywords: RANK; RANKL; ; Denosu - functions 3,9 . Research is focusing on drugs that target mab; Postmenopausal osteoporosis. the remodeling cycle acting in OC, OB and osteocytes or molecules that control the signaling pathway for cell functioning and gene transcription 9. Examples of stu - IntroductIon dies on way include Glucagon-like peptide 214, inhibitors 15 , PTH1-28 16 , calcium-sensing Osteoporosis (OP) is a skeletal disease associated with receptors 17 , Wingless (Wnt)/ - catenin pathway 18 , scle - an imbalance in bone resorption and formation, which rostin and Dickkopf-1 19 , activin ( ACE- turns to a loss of bone mass and deterioration of bone -011) 20 . However, the discovery of the receptor activa - microarchitecture 1. This results in low bone mineral tor of nuclear factor KB ligand (RANK ligand, RANKL) density (BMD) and poor bone quality, reduced bone osteoprotegerin (OPG) and RANK as a RANKL/OPG/ /RANK signaling pathway for the bone balance brought advances to the understanding of healthy bone turno - 1. Serviço de Reumatologia do Centro Hospitalar de Lisboa ver, and to osteolytic and destructive bone diseases like Ocidental, Hospital de Egas Moniz, EPE 2. CEDOC - Faculdade de Ciências Médicas, Universidade Nova OP, rheumatoid arthritis (RA), Paget’s disease of bone 10,11 de Lisboa and metastatic bone diseases . RANKL was identi -

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FIGurE 1. Bone remodeling sequences in healthy individuals. The bone remodeling unit (BRU) includes a sequence of events, during which osteoclasts (OC) resorb bone over a period of 3 weeks, creating cavities that are known as remodeling space. The resorption is followed by osteoblast (OB) activation and osteoid formation, filling the cavities over FIGurE 2. Control of osteoclastogenesis. Osteoclast (OC) a period of 3 months. When the matrix synthesis is finished differentiation is a contact-mediated process controlled by OB become embedded in the matrix as osteocytes (that will (OB). Membrane-bound receptor activator of 3,9 function as mechanoreceptors) . Legend: BRU – bone nuclear factor kB (RANK or RK in the figure) ligand (RANKL remodeling unit; CL – cement line; LC – lining cells; or RKL in the figure) derived from OB and is necessary for OC OB – osteoblast; OC – osteoclast; OS – osteoid differentiation. OB expression of RANKL is induced by hormones [e.g. parathyroid hormone (PTH) or cytokines (IL-6; PTH related protein)] and reduced by estrogen whereas fied as a potential target for therapeutic intervention in osteoprotegerin (OPG) is suppressed by glucocorticoids or PTH. Soluble RANKL is also produced by activated T cells. the treatment of these diseases. Possible strategies to - α (TNF α) stimulate RANKL release down-regulate RANKL include inhibition of RANKL from OB and act on progenitors primed by RANKL to amplify production, stimulation of endogenous OPG, and ad - osteoclastogenesis (with a gene transcription NF-kB mediated) ministration of exogenous OPG, soluble RANK or an - in inflammatory conditions. RANKL and interleukine-1 (IL-1) tibody to RANKL 2 (Figure 2). Denosumab (Prolia®, act on OC to prevent their apoptosis. The postmenopausal decline in estrogen levels leads to overproduction of RANKL AMG 162; Inc., Thousand Oaks, California, and increased OC-mediated bone resorption. The critical USA) is a fully human (IgG2 im - RANKL/RANK interaction is therapeutically disrupted by munoglobulin isotype) with a high affinity and speci - RANKL-specific monoclonal antibodies (denosumab) ficity for RANKL 2,3,11 , currently approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA) for clinical use in postmenopausal wo - amount of bone loss is proportional to the number of men OP with high risk of fracture and for the treat - BRUs activated at the bone surface at a given time 10 . In ment of bone loss associated with hormone ablation in the healthy adult, more than 1 million BRUs are active men with prostate cancer 11,21 . and up to 5-10% of existing bone is replenished an - This manuscript reviews Denosumab pharmacolo - nually. Full skeletal regeneration is accomplished once gical and clinical data in postmenopausal osteoporo - every decade 21 . High bone turnover diminishes bone sis, with a previous physiopathology overview. strength independently of BMD, because excessive num ber of resorption cavities act as areas of stress that may be a source of microcracks 2,3,11 . This high turnover AduLt sKELEton can eventually result in osteopenia or osteoporosis 3.

PhysIoLoGy rAnKL/oPG/rAnK sIGnALInG PAthwAy The adult human skeleton is a metabolically organ with OB are mononuclear cells responsible for the deposi - a coupled bone turnover that maintains the equili - tion of bone matrix and for OC regulation. They ori - brium in the trabecular and cortical bone. The total ginate from mesenchymal stem cells (MSC) by the ac -

ÓRGÃO OFICIAL DA SOCIEDADE PORTUGUESA DE REUMATOLOGIA 303 Denosumab: upDate

tion of transcription factors like core binding factor α1 ablation resulting in osteoporosis 24-27 . The Wnt signa - (Cbfa-1 ) also known as Runx2, osterix (Osx), activa - ling in OB is also a source of OPG regulation. This ting transcription factor 4 (ATF4), and bone morpho - pathway integrated with RANKL/OPG/RANK enabled genic proteins (BMP) as BMP4 22 . OC are derived from to understand the normal and diseased bone 11 . Many mononuclear precursors in the myeloid lineage of he - familiar bone diseases are mediated by RANKL/OPG/ matopoietic cells that also originate macrophages. Ma - /RANK pathway 21 (Table I). Evidence is accumulating crophage-colony stimulating factor (M-CSF) expres - that bone remodeling is modulated through the inte - sion by osteoblastic stromal cells is required for pro - raction of OC and OB with immune cells, cytokines genitor cells to differentiate into OC, but is unable to and circulating hormones 28 . It was demonstrated that complete this process by its own 23 . The principal final activated T cells directly stimulate osteoclastogenesis mediator of osteoclastic bone resorption is RANKL, through RANKL, and RANKL prolongs the survival of highly expressed by OB and T cells (mainly T helper dendritic cells and thereby increases T cells activity 29 . cells 17) 3. RANK is located on the cell membrane of and malignancy concerns have been raised OC and pre-OC and is a receptor for RANKL. by inhibiting RANKL, however it seems that RANKL/ RANKL/RANK binding stimulates OC differentiation /OPG/RANK system does not have an essential role in and survival, resulting in increased bone resorp - immune function of adults, who already have a fully tion 3,11,21 . OPG is a “decoy receptor” for RANKL, pre - developed 30 . venting its interaction with RANK, OC differentiation, activation of mature OC and permits OC apoptosis 3,21 PostmEnoPAusAL ostEoPorosIs (Figure 2). RANKL/OPG ratio represents an important Estrogen is a positive regulator of OPG expression and determinant of bone resorption. This ratio is decreased its decrease in postmenopausal women are associated by estrogens, interleukin-4 (IL-4), IL-13, interferon- γ with increased RANKL expression, which shifts the (IFN- γ), transforming - ( TGF- ), and in - bone remodeling balance toward the bone resorp - creased by glucocorticoids, PTH, PTH-related protein, tion 31 . The incidence of postmenopausal OP is growing prostaglandins, IL-1, IL-17, tumor necrosing factor- α due to changing demographics and increasing life ex - (TNF- α), 1,25- dihydroxyvitamin D (1,25vitD) and pectancy, which will also increase its economic and so - BMP 23,11,21 . The precise role of the RANKL/OPG/RANK cial burden fracture-related 31,32 . OP fractures occur mo - signaling pathway in regulating bone remodeling and re frequently in women, its frequency increases with mass was validated by gene studies in mice, with ge - age, and spine, hip and wrist are the skeletal sites ty - netic RANKL or its receptor deficiency and OPG over- pically associated to OP 31 . Vertebral fractures may re - expression resulting in osteopetrosis, and genetic OPG sult from relatively mild trauma in osteroporosis and

tAbLE I21 . rEvIEw oF thE dIsEAsEs mEdIAtEd by dIsruPtIons In rAnKL/oPG/rAnK sIGnALInG PAthwAy

RANKL/OPG/RANK-mediated diseases Mechanism(s) Postmenopausal osteoporosis ↑ bone marrow stromal cell expression of RANKL Primary hyperparathyroidism ↑ RANKL, ¯ OPG expression by osteoblasts Bone Paget’s disease ↑ stromal cell expression of RANKL Rheumatoid Arthritis ↑ RANKL expression by synoviocytes and T cells Periodontal bone loss ↑ RANKL expression by activated T cells Myeloma bone disease ↑ RANKL expression by myeloma cells Osteolytic bone metastases ↑ RANKL expression by tumour cells Humoral hypercalcaemia of malignancy Parathyroid hormone related protein (PTHrP) mediated: ↑ RANKL, Ø OPG by osteoblasts Familiar expansile osteolysis Activating mutations of the RANK gene Idiopathic hyperphosphatasia (Juvenil Paget’s disease) Inactivating mutations of the OPG gene

Legend: OPG – osteoprotegerin; RANK – receptor activator of nuclear factor kappa B; RANKL – receptor activator of nuclear factor kappa B ligand.

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are associated to an increased risk for subsequent frac - clearance is probably by the reticuloendothelial sys - ture. Hip fractures are associated with worst outcomes tem and no significant amount of denosumab seems to and secondary complications, and their risk increases be filtered and excreted by the kidneys 35 . Subcuta - in women from the age of 70 years 31-33 . Healthcare costs neous administration is characterized by 3 stages: a due to OP are difficult to calculate as they include the prolonged absorption phase with the maximum serum costs of acute hospital care, loss of working days for fa - concentration (at 5-21 days post-dose) increasing dis - mily carers, longterm care and medication 31-33 . The In - proportionately than the increase in dose; a long du - ternational Osteoporosis Foundation (IOF) estimated ration phase with half-life of a maximum of 32 days; a that the number of osteoporotic fractures in 2000 was rapid terminal phase when serum concentration is lo - 3.79 million and the total direct costs resulting from wer than 1000ng/ml 36 . The long duration of denosu - these fractures was estimated at €31.7 billion, which mab activity is probably due to a combination of a long is expected to increase to €76.7 billion by 2050 34 . Pre - half-life and a very potent antiresorptive effect at ear - vention of osteoporosis-related fractures appears to be ly stages of OC differentiation 2,10 . A feature that dis - essential to the quality of life and independence of pos - tinguishes denosumab from biphosphonates is the ra - tmenopausal women and prevent the economic bur - pid reversibility of its antiresorptive effect once it has den 32-34 . been eliminated and OC regeneration has occurred, since it is not incorporated in the bone matrix as the biphosphonates 3. Its capacity to reduce bone resorp - ostEoPorosIs trEAtmEnt: dEnosumAb tion was measured by serum C-telopeptide (CTX-1), As A nEw oPtIon by 82% within 72 hours post-dose, with a sustained ef - fect during the 6-month dosing interval 37 . The ideal anti-osteoporotic agent would have to meet the following favorable biological properties: a rapid PrE-cLInIcAL studIEs onset action, long duration effect, patient’s complian - The preclinical studies evaluating the RANKL/OPG/ ce and persistence, documented cost-effectiveness and /RANK role in bone showed: RANKL induces OC-like excellent safe profile 10,11 . Denosumab is a fully human cells formation in cell cultures 38 , recombinant OPG in - monoclonal immunoglobulin G2 antibody that binds hibits OC differentiation in a dose-dependent man - with high affinity and targets the activity of human ner 39 , osteotropic hormones and cytokines regulate RANK ligand , preventing it to interact with RANK on RANKL and OPG expression in human-derived OB the OC surface, which turns into the disruption of cel - cell lines 40 , OPG knockout mice develop OP and fra - lular signaling of bone resorption OC-mediated 3,10,11,31 . gility fractures 41 , RANKL and RANK knockout mices Denosumab inhibits numerous aspects of OC diffe - have osteopetrosis with the total absence of OC 24,25,42,43 . rentiation and function (fusion, differentiation, at - Human monoclonal antibodies (mAbs) are the fastest- tachment to bone, activation and survival), by inhibi - -growing category of mAb therapeutics entering clini - ting the intracellular signal pathways that are activated cal studies 44 . Murine antibodies are easier to produce, by the RANKL /RANK binding 10 . Denosumab does not but are limited by safety issues and diminished effica - bind to murine RANKL1, and does not cross-react with cy owing to the immunogenicity of the mouse-derived other human proteins of similar structure to RANKL, protein sequences 44,45 . One path started to develop such as TNF- α, TNF- , TNF-related apoptosis-indu - mAbs containing a combination of rodent-derived and cing ligand (TRAIL) or CD40 ligand 11,31 . human-derived sequences, resulting in chimeric and humanized mAbs. During the 2000s, human mAbs PhArmAcoKInEtIcs And mEtAboLIsm stand for 45% of the mAb candidates in the clinic and The pharmacokinetics of denosumab is nonlinear with 88 are now in clinical development. Denosumab is one dose. Although the absorption, , distri - of the 7 mAbs currently approved for marketing in the bution, and elimination are not well defined, studies United States 44-46 . Denosumab was generated by im - with similar IgG antibodies showed that subcutaneous munizing the XenoMouse with full-length human denosumab is absorbed by the lymphatic system with RANKL protein, producing a fully human IgG1 mAb subsequent drainage into the vascular system 2,3 . The known as AMG 161. Because human IgG1 can direct bioavailability is probably 50-100% with a distribu - complement-dependent cytotoxicity or antibody-de - tion that is about the same as the plasma volume, the pendent cell cytotoxicity to target cells, appeared the

ÓRGÃO OFICIAL DA SOCIEDADE PORTUGUESA DE REUMATOLOGIA 305 Denosumab: upDate

concern that AMG 161 could have a toxic profile cau - clinical studies. sed by death of RANKL-producing cells. It was con - PHASE 1: a phase 1 study was conducted in 49 heal thy verted to noncytotoxic IgG2 mAb, AMG 162, with postmenopausal women who received a single subcu - high affinity for human RANKL 45,48 . The difficulty of taneous dose of denosumab 0.01, 0.03, 0.1, 0.3 and AMG 162 to recognize rodent RANKL has complica - 3.0 mg/kg or placebo. All the cohorts had a follow-up ted pre-clinical studies and the relevant data were ob - of 6 months, except the highest doses (0.1, 0.3 and tained from cynomolgus monkeys 45 . The majority of 3.0 mg/kg) that were followed 9 months. Pharmaco - the preclinical studies in RANKL inhibition in mice logical effect was assessed by urinary N-telopeptide and rats used other agents than denosumab. The most (NTX) and seric serum bone-specific alkaline phos - commonly used were fusion molecules of recombinant phatase (BSAP) levels. Rapid and reversible NTX re - OPG or RANK and the Fc fragment of IgG, called OPG- duction was sustained for 6 months. Later BSAP re - -Fc or RANK-Fc, respectively 3. These studies de - duction occurred with a lesser magnitude. Denosu - monstrated that recombinant OPG prevents bone loss mab was well tolerated with no drug-related serious in ovariectomized (OVX) rats 39 , recombinant OPG de - adverse events (SAEs) reported or study discontinua - creases OC differentiation in normal mice, resulting in tion due to AEs. Infectious events were similar in both non-lethal osteopetrosis 39 , recombinant OPG prevents groups (33% in placebo versus 38% in denosumab). bone loss in mice with low BMD that over-express Two hospitalizations: severe undetermined abdominal TNF- α49 , RANKL inhibition increases bone minerali - pain (in the 0.01mg/kg group) and a cholecystitis (in zation and improves mechanical strength in the femur the 0.1 mg/kg group). Mild transient dose-dependent of young male rats 50 , in aged OVX rats a combination decrease in albumin-adjusted serum calcium and dose- of rat OPG and PTH increased BMD more than either dependent early increase in PTH levels 36 (Table II). agent alone 51 . PHASE 2: a randomized phase 2 study was performed In the cynomolgus monkeys the preclinical studies to evaluate the efficacy and safety of denosumab com - showed: 5-year-old male monkeys treated with deno - pared with alendronate or placebo, in postmenopau - sumab had an increased bone mass and improved sal women with low bone mass (lumbar vertebra bone strength in femur and lumbar vertebral bodies 52 , T-score:-1.8 to -4 or total hip or femoral neck T-score: skeletal benefits were demonstrated with the RANKL -1.8 to -3.5). The 412 patients enrolled in this study inhibition in RA models 53 , ovariectomy models 54 , mul - were randomized to receive subcutaneous denosumab tiple myeloma models 55 and inflammatory bowel di - 6, 14, or 30 mg every 3 months; 14, 60, 100, or 210 sease models 56 . Knocking technology has been recen - mg every 6 months; open-label alendronate 70 tly used to create a genetically engineered mouse ex - mg/week; or placebo for 24 months. Primary endpoint pressing a chimeric form of RANKL (human/murine) was the percent change in BMD at the lumbar spine at that is bound and neutralized by denosumab, which 12 months compared to baseline. At 12 months de - has been studied for evaluating the skeletal effects of nosumab group achieved an increase of 3.0 to 6.7% in denosumab in different circunstances 57,58 . lumbar spine BMD compared to baseline, with a dose- dependent rapid and sustained decrease in the bone turnover markers (BTMs). At 24 months the patients cLInIcAL studIEs on continued the study with a 60mg subcutaneous de - PostmEnoPAusAL ostEoPorosIs nosumab dose each 6 months and were randomized to continue treatment for 24 months, discontinue, or The first study of RANKL inhibition in was switch to placebo for 12 months and resume denosu - conducted with OPG-Fc, a phase 1 randomized, dou - mab treatment for 12 months. The 48 months deno - ble-blind, placebo-controlled, sequential dose escala - sumab group treatment showed an increase in BMD at tion study in healthy postmenopausal women. Each the lumbar spine (9.4% to 11.8%) and total hip (4.0 of the 52 subjects received a single subcutaneous dose to 6.1%) with the BTMs remaining suppressed, while of OPG-Fc 0.1, 0.3, 1.0, 3.0 mg/kg or placebo. It was the placebo group showed a loss of 2.4% and 3.5% at shown that a single dose of OPG-Fc caused a rapid, the spine and hip, respectively. Within the first 12 reversible and dose-dependent suppression of bone months of denosumab discontinuation BMD decrea - resorption, with no adverse events (AEs) or neutrali - sed 6.6% in the lumbar spine and 5.3% in total hip. Re - zing antibodies 59 . This provided support for further treatment with denosumab at month 36 increased

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ÓRGÃO OFICIAL DA SOCIEDADE PORTUGUESA DE REUMATOLOGIA 307 Denosumab: upDate r . a t

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f l r r n

o d

E E d o a c l l – n r

e

l l u A A l treatment. By month 48, BMD in - r a S a a p q a

S S

a r r

s s L r

s l

e e y p e p p ; d d a t

E creased 9% at the lumbar spine and v v n r k u u

n n i e m e o A o c

f o o a a

o e h

m r r o a r r r 3,9% at the total hip from baseline

c s s n p s g g b a a a

i e

l l l l E E r s e i i i n a y h h e c E r A A o and the BTM values were similar to t t e p

a

m m m o b

l o f f o i A i i

K – S b o S p S S o b c m

i those of the continuous treatment e r T f t

C e -

group. In 3.2% of denosumab pa - d Q s m d e

N d t p % d e u l l

e F u l n s e ; 5 a

i

r

tients occurred , all were u o ; d n a r c

n r 0 p ) s i s l u v e

. s e e b e u

t s u e u a s

r c e t 1 % e i – d r r n a common community-acquired (no m

e c o s

t a n u

0 d e r r s e i b r o o a e n

a C d r

y 4 g v i e e c u r e

r s w

o e c

(

t m t

r

opportunistic infections), with re - v g t

M r l

b e r l a

b b b c

c n

l t % a B a f p a e l c a a a a i a t a i n n d s i v 9

o v r a s s i

. f h

i quired hospitalization solved with m

f o

h u

; n m m m o f n t i

l t

1 r a d t k a u

, t e D u u u

a

a ( o

e t i s p s

) )

t s s s s – i t )

s

n standard antibiotics. This original o

n o M y e r t o o

o a % % D D l n

n e e B N R N M n e d n n n

t e 0 8 a e e n r e L L D c K M M T e e e r n x study was extended 4 additional 2 k 6 E

i h m ; d ( G s B t ( T D A d a d B A e B r t t d s m e e

o years with all patients switched to t d t y m p A

t n n

u

i s

– e l E l t e

denosumab 60 mg/6 months sub - t d f o b a r w d a

n n -

v i W i e s

e t e e a

c

l

r D –

o cutaneous and a further analysis 2

n n M

d

b n i S s e u p i l P I c

M t u D n

L n i e d ; s

c o s a B years after (6 years of denosumab r s n , o s M

n a t h i d i a o

b

t r g B s e e n N

f

b – i v r o , n n n

treatment) reported an BMD in - F r i y l m ;

o o s l o B D r o a , i p o m e e t i r a P p D m o g h

H M

c crease of 13.3% at the lumbar spi - d h

b o ; r o

p m n s e B o e f T u l 2 i t r

E r

t a a d 1 r s r e t e o m t ne with sustained suppression of R h e H o e P o k t e h s t r l C D m v t R T r a

37,60-62 a a o – BTMs (Table II). s

m u L

s s s H r a h h h

A HASE n T e

P 3: p t t t

v ; s o y o n n n i e o n d t u s o o o REATMENT OF POSTMENOPAUSAL n T e a u o r A t r m m m d m u

P - t t S u

OSTEOPOROSIS s e 2 6 2 o l d e o 1 3 1 g n p n

n o “Fracture Reduction Evaluation of

i E

– ; b s

l

d d

m

a – – a a O b b ;

s Denosumab in Osteoporosis Every t e e - n - s a a o

c M D s ; o i h h n n 63 b l i P S M t - - m m

o o o t e

a 6 Months” (FREEDOM) , rando - ; s ; T o o u u i a i c n n s P a t t r B s s

t i

r - - a n

t , , t O l ; o o n e

r r d d mized 7668 postmenopausal wo - n B B y t I e p e e n n I a a t I M

c t v

i e e D D n I e e s e s i a P

n b d d

, ,

men with osteoporosis into 2 v h h i r n e f

r r f e

e a A ; ; s , s o e e n n o b l

r d a t t y y

h t

a o o a m e t t groups: placebo or subcutaneous t l c h n n i i t s s n v

a i i n

r r e e u e m p o r d r r y

e c c o o s e u v a t N N a a denosumab 60mg/6 months. Pri - m - - i i d

i s i i s n r r m o s o L L p p i t t u p t e o e e l l u

t f f A A n a m , g m n m m mary endpoint was a reduction in o

u u

S

r e i n n E T e r s s o o e i i r r a a v M c l R d M - t - c v d e l n

s the incidence of new radiographic o o

F p b – 0

. o s – –

h

vertebral fractures in a 3-years pe - 4

t

- E I

S s H

S o D e A d L L e M ≥ T L b riod. Secondary endpoints were re - n S r

M n

t

i P A t t ; r

l a o I B o a l ;

a a t o c e ; a

r

d duction in hip and other nonverte - i s 5 s e H H e r 0 0 . - 0 t S t l a s . . t .

l a T T T

2 L I e

2 4 B 2 - o

I n t d bral fractures and changes in BMD - - r r - r t I i e o t

≤ o o ≥ s < < a r z n i E d

and BTMs. Denosumab group pre - o s

n m c

e - n o A

l W c o a d a i e sented a 68% reduction in new ver - s s h

b t e n r

s

M t v - - e ; ï P a r o a c h P n c

r m N r a i a

t e

D tebral fracture risk compared to pla - a

e i E L o l e c n n i y – d i

t p y e p A M h w t

n a

3 T ; - o p

B cebo (2.3% vs. 7.2%; p<0.0001), o t . s 6 W a s

R p d

e r . o r

C t

2

t e ; F e r o f a 7 w P n M t s 7 t y

e

e 40% reduction in the hip fracture e p o 6 ; o a o o P s ; h

l

v y

e b o e ;

o l

p e e r E 8 9 e

W a b t h 4 g m t

N (0.7% denosumab vs. 1.2% place - e r 6 8 4 . t a e s a m s i l u L g M r 8 1 0 4 i r o o u a e 7 1 5 w 6 - P p A N bo; p=0.036), and 20% reduction v v s m a d E

o 3 t a t 6

in the nonvertebral fractures risk r o

– d . n 5

M I e

6 s t I 6

– (6.5% denosumab vs. 8.0% place - I 6 O E E

u

p A D A D D E

y I : L E bo; p=0.011). Denosumab group m N N d

d C o ; E b A n c u e E

e R t A T showed a significantly increase in n e g i F S t S D v e p i t s L BMD at all skeleton, mainly in the

ÓRGÃO OFICIAL DA SOCIEDADE PORTUGUESA DE REUMATOLOGIA 308 inÊs silva e col.

forearm. No differences of total incidence of AEs or tal hip T-score of -2.0 to -4.0. The primary endpoint SAEs were reported in both groups. The incidence of se - was percent change in BMD at the total hip at 12 rious infections was similar in both groups. Infections months for denosumab compared to alendronate. The resulting in death were 0.2% in both groups. Few de - study design allowed testing the primary endpoint for nosumab patients were diagnosed endocarditis (n=3), superiority if noninferiority was demonstrated. At 12 pancreatitis (n=8), eczema was reported in 3% of de - months denosumab group presented a significantly nosumab group versus 1.7% in placebo group greater increase in BMD at the total hip (denosumab (p<0.001). Cellulitis as an SAE occurred in 0.3% 1.9% vs. alendronate 1.05%; p<0.0001), lumbar spi - (12/3886) in the denosumab group versus less than ne, and distal one-third radius, compared with conti - 0.1% (1/3876) in the placebo group (p=0.002). This nuing of alendronate. AEs and SAEs were similar in study was extended for 2 years with all patients swit - both groups. Authors concluded that postmenopausal ched to open-label denosumab 60 mg/6 months (with women with low BMD can be safely transitioned from a significantly CTX-1 reduction and BMD increase 64 ), weekly oral alendronate to 6-monthly subcutaneous and then it was extended 5 more years to complete a to - denosumab to achieve an incremental increase in bone tal of 10 years of denosumab exposition. Authors con - mass. cluded that denosumab given subcutaneously twice yearly for 36 months reduced the risk of new vertebral, nonvertebral and hip fractures in women with OP. FurthEr cLInIcAL studIEs Histology and Histomorphometry with Denosumab HEAD -TO -HEAD COMPARISON WITH ALENDRONATE Reid et al 67 , collected iliac crest biopsies from FREE - “Determining Efficacy: Comparison of Initiating De - DOM and STAND populations, after 12, 24 and 36 nosumab Versus Alendronate” (DECIDE) 65 , a double- months of denosumab exposition. In the FREEDOM -blind, double-dummy noninferiority 1-year study to study median eroded surface was reduced by greater compare the effects of denosumab and alendronate on than 80% and OC were absent from greater than 50% BMD and BTM in naïve postmenopausal women of biopsies in the denosumab group. It was shown a (n=1189) with T-score of lumbar spine or total hip reduction in fractures in the same cohort of patients in <-2. Patients were randomized to receive subcutaneous whom there was such a clear histological evidence of denosumab 60mg/6months plus oral placebo/week or reduced turnover. In STAND study, the histomorpho - oral alendronate 70mg/week plus subcutaneous place - metry indicates that denosumab 60mg/6months pro - bo/6months. The primary endpoint was percent chan - duces greater inhibition of turnover than occurs with ge from baseline in total hip BMD at month 12 and the alendronate 70mg/week, but without evidence of any secondary endpoints were percent change in femoral untoward interaction after the transition from alen - neck, trochanter, lumbar spine and one-third distal ra - dronate to denosumab. dius BMD, and changes in BTM. Denosumab group showed a greater BMD increase at the total hip versus EFFEcts oF dEnosumAb on bonE placebo (3.5% vs. 2.6%; p<0.0001) and a greater re - mIcroArchItEcturE duction in BTMs compared to alendronate. The overall Seeman et al 68 , conducted a double-blind pilot study to incidence of AEs, SAEs, infections or was compare the effect of denosumab and alendronate on similar between both groups. Authors concluded that cortical and trabecular microarchitecture at the radius denosumab was associated with both significantly and tibia in postmenopausal women using a quantita - more reduction in bone resorption and greater gains in tive computed tomography (QCT) and a high-resolu - BMD at all measured skeletal sites compared to alen - tion peripheral QCT (HR-pQCT). The women were dronate. randomized to receive subcutaneous denosumab 60mg/6months (n=83), oral alendronate 70mg/week TRANSITIONING FROM ALENDRONATE TO DENOSUMAB (n=82) or placebo (n=82). Trabecular BMD and corti - “Study of Transitioning from Alendronate to Denosu - cal thickness at the distal radius at month 12 decrea - mab” (STAND) 66 , a randomized, double-blind, double- sed in the placebo group while was preserved in alen - -dummy, parallel-group, 1-year study in postmenopau - dronate group. Denosumab prevented the decline or sal women (n=504) previously treated with alendro - improved these variables. Similar results were achie - nate at least 6 months, and with a lumbar spine or to - ved in the tibia.

ÓRGÃO OFICIAL DA SOCIEDADE PORTUGUESA DE REUMATOLOGIA 309 Denosumab: upDate

dEnosumAb In PAtIEnts wIth rEnAL tAbLE Iv. rEPortEd dIFFErEncEs bEtwEEn ImPAIrmEnt dEnosumAb And thE bIPhosPhonAtEs Block et al 69 , conducted a phase 1 study to evaluate the pharmacokinetics, pharmacodynamics and safety of a Denosumab compared to biphosphonates single dose of 60mg subcutaneous denosumab in 55 • Denosumab blocks osteoclasts formation, function patients with different degrees of renal function. Re - and survival while biphosphonates cause loss of sults showed that the renal impairment did not affect resorptive function but “disabled” osteoclasts may the denosumab pharmacokinetics and pharmacody - persist 78 namics, and no dose adjustment is necessary in im - • Exerts its effect from within the extracellular fluid 67 pairment renal function. About 30% of patients with Rapid offset of action at about 6 months 11,57 severe renal function and hemodialysis showed symp - • Induces more rapid and greater reduction in bone tomatic hypocalcaemia. remodeling 63 • Superior pharmacokinetic properties (better bEsIdE PostmEnoPAusAL ostEoPorosIs distribution, no excretion of kidneys) 10 trEAtmEnt • Greater increase in bone mineral density 64 PREVENTION OF POSTMENOPAUSAL OSTEOPOROSIS • Positive effect on both cancellous and cortical bone 3,72 70 “Denosumab Fortifies Bone Density” (DEFEND) , was • Better strength indexes and geometrical bone variables 67,68 a randomized, placebo-controlled, trial to evaluate ef - • Completely reversible effect and no accumulation in ficacy and safety of denosumab in postmenopausal wo - bone 3 men with osteopenia. • Possible non-blunting effect on subsequent anabolic Denosumab is currently being studied for other in - therapy 10 dications as RA bone erosions, bone loss associated • Better patient’s convenience and compliance 1 with androgen deprivation therapy, bone loss associa - • Denosumab was the first anti-bone resorbing agent ted with aromatase inhibitor therapy and for the treat - that showed to halt bone erosions in Rheumatoid ment of bone metastases. However these studies are Arthritis 11 beyond the scope of this paper. sAFEty And toLErAncE lation model populated with cost and epidemiological In the DEFEND, DECIDE, and STAND studies, AEs data from Belgium and a base-case population defined and SAEs, including infections and malignancies, were from FREEDOM. It was concluded that denosumab is similar in both groups 33 . In DECIDE the most common cost effective compared with no treatment 74 and oral types of infections were nasopharyngitis, influenza and bisphosphonates 75 for postmenopausal Belgian women upper respiratory tract infections. In STAND were na - similar to FREEDOM population. Additional publis - sopharyngitis and bronchitis 1. In the FREEDOM study hed studies with data from England, Wales and Sweden the only significant AE were cellulitis and eczema 71,72 . concluded that denosumab has a higher probability of The longest exposure to denosumab reported to date being cost-effective in some patients subgroups 76,77 . A is 6 years. No significant differences in infections, neo - cost-utility analysis of denosumab versus standard care plasms were reported as SAEs for denosumab 11 . There (alendronate and colecalciferol) in the treatment of were no denosumab-related cases of osteonecrosis of post-menopausal osteoporosis in Portugal concluded jaw, fracture repair problems, changes in white blood that denosumab is a cost-effective therapeutic strategy cells counts, T, B, or natural killer cell counts, immu - with an Incremental Cost-effectiveness Ratio (ICER) noglobulins or antibodies to denosumab 1,11 . OF 14.887 € per Quality Adjusted Life Year (QALY) gained. The analysis was undertaken from a NHS pers - cost-EFFEctIvEnEss ProFILE pective, efficacy data for denosumab was taken from Affordability of a drug therapy is a concern for healthca - FREEDOM and the comparator was taken from a meta- re system and patients 73 . Hiligsmann et al 74 , assessed -analysis conducted by National Institute for Health the potential cost effectiveness of denosumab in the and Clinical Excellence (NICE). Epidemiological Por - treatment of postmenopausal osteoporotic women in tuguese data were complemented with Swedish data an updated version of a validated Markov microsimu - whenever the former were unavailable. The model pre -

ÓRGÃO OFICIAL DA SOCIEDADE PORTUGUESA DE REUMATOLOGIA 310 inÊs silva e col.

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10th IntErnAtIonAL conGrEss on sLE

Buenos Aires, Argentina 18 a 21 Abril 2013

ÓRGÃO OFICIAL DA SOCIEDADE PORTUGUESA DE REUMATOLOGIA 313