Tratamento da Tratamento da OsteoporoseOsteoporose

Mulheres na pós Mulheres na pós menopausamenopausa

Paula Miguel LaraPaula Miguel Lara

-Reumatologia--Reumatologia-

Use of selective estrogen receptor Use of selective estrogen receptor modulators in postmenopausal modulators in postmenopausal

womenwomen

• The role of postmenopausal hormone The role of postmenopausal hormone therapy for prevention of chronic therapy for prevention of chronic disease has been greatly diminisheddisease has been greatly diminished

• that that estrogen-progestin therapyestrogen-progestin therapy is is associated with an increased risk for associated with an increased risk for breast cancer, coronary disease, breast cancer, coronary disease, stroke, and venousstroke, and venous tromboembolismtromboembolism

• Synthetic estrogen receptor (ER) Synthetic estrogen receptor (ER) ligands such as ligands such as raloxifene and and tamoxifen represent an alternative for women represent an alternative for women suffering from menopausal symptoms.suffering from menopausal symptoms.

• Because these drugs Because these drugs bind with high bind with high affinity to the ERaffinity to the ER and possess tissue- and possess tissue-selective estrogen agonist and selective estrogen agonist and antagonist properties, they are called antagonist properties, they are called selective estrogen receptor selective estrogen receptor modulators (SERMs) modulators (SERMs)

RaloxifenoRaloxifeno

• Drugs that have estrogen activity in Drugs that have estrogen activity in bone and other systems but not in bone and other systems but not in reproductive tissue. reproductive tissue.

• In ovariectomized animals raloxifene In ovariectomized animals raloxifene preserves bone density, preserves bone density, lowers serum lowers serum total cholesteroltotal cholesterol, and inhibits aortic , and inhibits aortic cholesterol accumulation, cholesterol accumulation, without causing without causing endometrialendometrial hyperplasia hyperplasia

• 1145 healthy European and North 1145 healthy European and North American postmenopausal women, double-American postmenopausal women, double-blind, placebo-controlled trials with blind, placebo-controlled trials with random assignment to receive raloxifene random assignment to receive raloxifene hydrochloride, 30, 60, or 150 mg, or hydrochloride, 30, 60, or 150 mg, or placebo dailyplacebo daily

• Over Over two yearstwo years, , BMD increased BMD increased significantlysignificantly at all sites tested with each at all sites tested with each dose of raloxifene, while there was bone dose of raloxifene, while there was bone loss at these sites in the placebo group loss at these sites in the placebo group

• The mean difference in BMD between those receiving 60 mg of raloxifene daily and placebo was 2.4 percent for the lumbar spine and total hip and 2.0 percent for the total body

• (LDL)(LDL) cholesterol cholesterol decreased decreased significantly significantly in each of the raloxifene groups in each of the raloxifene groups compared with placebocompared with placebo

• total cholesteroltotal cholesterol decreased by decreased by 6.4 6.4 percentpercent versus versus 1.2 percent1.2 percent for placebo, for placebo, while serum while serum LDL LDL cholesterol decreased cholesterol decreased by by 10.1 versus 1.0 percent (diminui ICO)10.1 versus 1.0 percent (diminui ICO)

• There was also There was also no differenceno difference in in endometrial thickness, or in complaints endometrial thickness, or in complaints of breast pain or vaginal bleedingof breast pain or vaginal bleeding

• Hot flushesHot flushes occurred more often in the occurred more often in the raloxifene-treated patients (25 percent) raloxifene-treated patients (25 percent) than in the placebo-treated patients (18 than in the placebo-treated patients (18 percent).percent).

• This was the only significant side effect of This was the only significant side effect of raloxifene detected detected.

• Study 6828 of the women receiving 60 mg Study 6828 of the women receiving 60 mg and 120 mg and 120 mg raloxifene, , 6.6 and 5.4 percent6.6 and 5.4 percent, , respectively, had respectively, had new vertebral fracturesnew vertebral fractures, , compared with compared with 10.1 percent in the 10.1 percent in the placebo group; placebo group;

• the risk of the risk of nonvertebral fractures was nonvertebral fractures was similarsimilar in the three groups in the three groups

• Raloxifene did did not increasenot increase the risk of the risk of endometrial cancerendometrial cancer..

• But it did But it did increase increase the incidence of the incidence of thromboembolic disease (TVP e AVC thromboembolic disease (TVP e AVC fatal), hot flashes, influenza-like fatal), hot flashes, influenza-like symptoms, peripheral edema, and leg symptoms, peripheral edema, and leg crampscramps

• Potência:Potência:

• Raloxifene appears to be a appears to be a less potentless potent antiresorptive agent than antiresorptive agent than alendronate or estrogenor estrogen

• In a one-year study of 331 In a one-year study of 331 postmenopausal women with postmenopausal women with osteoporosis, osteoporosis, alendronate alendronate (10 (10 mg/day) increased BMD mg/day) increased BMD more thanmore than raloxifeneraloxifene (60 mg/day) (60 mg/day)

• Quando usar:Quando usar:

• Reserve the use of this drug for Reserve the use of this drug for patients who cannot tolerate patients who cannot tolerate alendronate and/or risedronate and/or risedronate

• Do not recommend raloxifene as the Do not recommend raloxifene as the first line drug because it has first line drug because it has less less antiresorptive action than the antiresorptive action than the bisphosphonatesbisphosphonates

• Eventos adversosEventos adversos

Parathyroid hormone therapy Parathyroid hormone therapy for osteoporosisfor osteoporosis

• PTH is an 84-amino acid polypeptide PTH is an 84-amino acid polypeptide secreted by the parathyroid glands in secreted by the parathyroid glands in response to relatively response to relatively small changes in small changes in serum calciumserum calcium

• (PTH1r) membrane surface receptor (PTH1r) membrane surface receptor expressed in multiple tissues including expressed in multiple tissues including cartilage, bone, breast and kidneycartilage, bone, breast and kidney

• Is one of the two major hormones Is one of the two major hormones modulating calcium and phosphate modulating calcium and phosphate homeostasis, the other being calcitriol homeostasis, the other being calcitriol

• Its actions to Its actions to stimulate renal tubular stimulate renal tubular calcium reabsorption and bone calcium reabsorption and bone resorptionresorption..

• Chronic exposureChronic exposure to high serum PTH to high serum PTH concentrations (as seen with primary concentrations (as seen with primary or secondary hyperparathyroidism) or secondary hyperparathyroidism) results in results in bone resorptionbone resorption. .

• Intermittent administrationIntermittent administration of of recombinant human PTH has been recombinant human PTH has been shown to shown to stimulate bone formationstimulate bone formation more than resorption, at least over more than resorption, at least over the the first 12 monthsfirst 12 months of treatment. of treatment.

• MECHANISMS OF ACTIONMECHANISMS OF ACTION

• PTH 1-34 (teriparatidePTH 1-34 (teriparatide, Forteo) , Forteo) "anabolic""anabolic" agents stimulate bone agents stimulate bone formation, activate bone remodeling formation, activate bone remodeling and are administered subcutaneously as and are administered subcutaneously as daily injectionsdaily injections 20mcg/day for the 20mcg/day for the treatment of severe osteoporosis treatment of severe osteoporosis

• PTH stimulates PTH stimulates preosteoblasts to preosteoblasts to maturemature into bone-forming osteoblasts into bone-forming osteoblasts that lay downthat lay down collagen collagen and and mineralize mineralize matrixmatrix

• Bone formation begins within the Bone formation begins within the first first monthmonth of PTH treatment and of PTH treatment and peaks six to peaks six to nine monthsnine months after initiation of daily PTH after initiation of daily PTH

• Markers of bone turnoverMarkers of bone turnover indicate that indicate that bone resorption in patients on PTH bone resorption in patients on PTH begins begins peaks after 12 monthspeaks after 12 months of of treatment treatment

• Most of the gains in BMD occur in the Most of the gains in BMD occur in the first few months, although first few months, although antifracture antifracture efficacyefficacy is evident only is evident only after six months after six months or moreor more of treatment of treatment

• The effects of PTH are The effects of PTH are dose-dependentdose-dependent, , such that higher daily doses result in such that higher daily doses result in greater increases in formation, and greater increases in formation, and subsequently higher BMD with treatment subsequently higher BMD with treatment

• Intermittent PTH treatment Intermittent PTH treatment enhances enhances trabeculartrabecular more than cortical more than cortical bone massbone mass

• Qualitative changes in trabecular Qualitative changes in trabecular micro micro architecture architecture

• The improvement in the The improvement in the mechanical mechanical strengthstrength of the skeleton and its of the skeleton and its resistanceresistance to fractureto fracture

• 1637 postmenopausal 1637 postmenopausal women with previous vertebral fractures were randomly assigned to receive PTH (20 or 40 mcg/day subcutaneously) or placebo.

• After 18 months of treatment, 20 mcg 20 mcg group, when compared to placebo, BMD group, when compared to placebo, BMD increased by increased by 9 and 39 and 3 more more percentage percentage pointspoints in the lumbar spine and femoral in the lumbar spine and femoral neck.neck.

• 40 mcg group, when compared to placebo, BMD increased by 13 and 6 more percentage points in the lumbar spine and femoral neck

• The main The main adverse effectsadverse effects of PTH were of PTH were nausea, headache, and nausea, headache, and hypercalcemia, occurring more hypercalcemia, occurring more commonly at the higher dose.commonly at the higher dose.

• Fracture Prevention Trial (Fracture Prevention Trial (FPT), FPT), 1600 women with prior vertebral 1600 women with prior vertebral fractures receiving PTH 1-34 (20 mcg fractures receiving PTH 1-34 (20 mcg or 40 mcg/day) or placebo, there was or 40 mcg/day) or placebo, there was significant vertebral and non-significant vertebral and non-vertebralvertebral fracture efficacy fracture efficacy

• Fracture risk reduction did not differ Fracture risk reduction did not differ by dose, even though BMD changes by dose, even though BMD changes were significantly greater with 40 were significantly greater with 40 mcg/day mcg/day

• The Fracture Prevention Trial, PTH administration decreased vertebral fracture rates by 65 to 75 percent

• The percentage of vertebral fracture The percentage of vertebral fracture reduction that reduction that could be attributedcould be attributed to to the improvement in spine the improvement in spine BMD BMD was was only 30 to 40 percent only 30 to 40 percent

• Non-BMD determinantsNon-BMD determinants of bone of bone strength:bone geometry, strength:bone geometry, microarchitecture, remodeling rate, microarchitecture, remodeling rate, damage accumulation, and/or damage accumulation, and/or collagen/mineral matrix propertiescollagen/mineral matrix properties

• COMBINATION THERAPY COMBINATION THERAPY

• PTH plus bisphosphonate therapy - PTH plus bisphosphonate therapy - nono additional benefit for spine or hip additional benefit for spine or hip BMD compared with PTH aloneBMD compared with PTH alone    

• In patients who are taking raloxifene In patients who are taking raloxifene but require additional therapy, it is but require additional therapy, it is unclearunclear whether teriparatide should be whether teriparatide should be added to or replace raloxifene.added to or replace raloxifene.

• Up to date do not recommend Up to date do not recommend combination therapy with raloxifene combination therapy with raloxifene and teriparatide. and teriparatide.

• Fracture Prevention Trial after discontinuation of teriparatide were followed for an additional 18 months in an open label extension.

• Women who were initially randomized to PTH still had a 40 percent relative risk reduction in vertebral fractures during the follow up 18 month period

• The gains in hip and spine BMD with PTH decline following PTH discontinuation

• Treatment with Treatment with alendronatealendronate during during that year that year following PTHfollowing PTH, preserved the , preserved the increase of 30 percent in trabecular increase of 30 percent in trabecular BMD gained in the first year by PTH BMD gained in the first year by PTH

• Potential candidates for PTH therapy Potential candidates for PTH therapy includeinclude

• Men or postmenopausal women with severe osteoporosis (T-score of -3.5 or below even in the absence of fractures; T-score of -2.5 or below plus a fragility fracture).

• Patients with osteoporosis who are Patients with osteoporosis who are unable unable to tolerate bisphosphonatesto tolerate bisphosphonates or who have or who have relative contraindications to relative contraindications to bisphosphonates (achalasia, scleroderma bisphosphonates (achalasia, scleroderma esophagus, esophageal strictures). esophagus, esophageal strictures).

• Fail other osteoporosis therapies Fail other osteoporosis therapies

• NotNot used as a used as a first-line drugfirst-line drug for for treatment or prevention of osteoporosis.treatment or prevention of osteoporosis.

• ADVERSE EVENTS

• Hypercalcemia Hypercalcemia and and hypercalciuriahypercalciuria are the are the two most common side effects of both two most common side effects of both

• Only 3 percent had persistent hypercalcemia requiring dose reduction

• Hypercalcemia was more common Hypercalcemia was more common with the 40 mcg dose (which is not with the 40 mcg dose (which is not currently approved or available). currently approved or available).

• PTH should not be used in individuals with renal stones or persistent hypercalcuria.

• Occasional hypotension or tachycardia can occur with the first few doses

• NauseaNausea and and headacheheadache; muscle ; muscle crampscramps

• Serum Serum uric acid increasesuric acid increases; an attack of ; an attack of goutgout

• Of more than 300,000 patients Of more than 300,000 patients worldwide treated with Forteo, there worldwide treated with Forteo, there has been one reported case of has been one reported case of osteosarcomaosteosarcoma in a postmenopausal in a postmenopausal women taking Forteo women taking Forteo

• Study in Study in rats, osteosarcoma occurred in higher doses and long duration

• Pretreatment evaluation  Pretreatment evaluation 

• Serum Ca, P, creatinine, alkaline Serum Ca, P, creatinine, alkaline phosphatase, albumin, 25-phosphatase, albumin, 25-hydroxyvitamin D, uric acid hydroxyvitamin D, uric acid

• 24-hour urine Ca, creatinine 24-hour urine Ca, creatinine

• vitamin D deficient should be replaced vitamin D deficient should be replaced with vitamin D prior to starting PTH with vitamin D prior to starting PTH therapy therapy

• uric acid pre-treatmenturic acid pre-treatment

• Precautions Precautions

• Primary or secondary hyperparathyroidism Primary or secondary hyperparathyroidism should not receive PTHshould not receive PTH

• Patients who are at increased baseline risk Patients who are at increased baseline risk for osteosarcoma, such as those with for osteosarcoma, such as those with Paget disease of bone, history of prior Paget disease of bone, history of prior radiation therapyradiation therapy

• Pre-existing malignancies, renal stones, Pre-existing malignancies, renal stones, gout, or renal insufficiency gout, or renal insufficiency

Strontium ranelateStrontium ranelate    • Inhibit bone resorption and increase bone Inhibit bone resorption and increase bone

formationformation

• Two-year clinical trial of 353 Two-year clinical trial of 353 postmenopausal women with osteoporosis postmenopausal women with osteoporosis and at least one vertebral fracture who and at least one vertebral fracture who were randomly assigned to receive were randomly assigned to receive strontium ranelate or placebo strontium ranelate or placebo

• lumbar spine lumbar spine mineral density increasedmineral density increased in in a dose-dependent manner (maximum a dose-dependent manner (maximum effect was with the highest dose used, 2 effect was with the highest dose used, 2 g/day)g/day)

• In the second year of the study, the In the second year of the study, the risk of new vertebral fracturesrisk of new vertebral fractures decreaseddecreased in the 2 g/day group. in the 2 g/day group.

• 1649 postmenopausal1649 postmenopausal women with women with osteoporosis and at least one osteoporosis and at least one vertebral fracture were randomly vertebral fracture were randomly assigned to receive strontium assigned to receive strontium ranelate (2 gm/day) or placebo for ranelate (2 gm/day) or placebo for three yearsthree years

• New vertebral fracturesNew vertebral fractures was was decreased decreased significantly by significantly by 41 percent41 percent during the three-year study period during the three-year study period

• Bone mineral density at the LS, Bone mineral density at the LS, increased by increased by 8 percent8 percent compared with compared with the placebo group. the placebo group.

• A meta-analysis of four trials - A meta-analysis of four trials - evidence that strontium ranelate is evidence that strontium ranelate is effective for effective for reducing the risk of reducing the risk of vertebral fracturesvertebral fractures, and to a , and to a lesser lesser extent, non-vertebralextent, non-vertebral fractures fractures

• Effective and well-tolerated therapy.Effective and well-tolerated therapy.

Denosumab Denosumab  • RANKLRANKL, a member of the TNF superfamily, , a member of the TNF superfamily,

is essential for the function of bone-is essential for the function of bone-resorbing osteoclasts;resorbing osteoclasts;

• RANKL RANKL accelerates osteoclastogenesisaccelerates osteoclastogenesis when it binds to its receptor, when it binds to its receptor, RANKRANK, but is , but is blocked by blocked by osteoprotegerinosteoprotegerin, which is , which is produced by osteoblasts produced by osteoblasts

• Denosumab is a Denosumab is a humanized monoclonal humanized monoclonal antibodyantibody against RANKL that reduces against RANKL that reduces osteoclastogenesisosteoclastogenesis

• A phase 2 trial of 412 postmenopausal A phase 2 trial of 412 postmenopausal women receive denosumab (at a dose women receive denosumab (at a dose of 14, 60, 100, or 210 mg of 14, 60, 100, or 210 mg subcutaneously every three or six subcutaneously every three or six months), open-label alendronate (70 months), open-label alendronate (70 mg once weekly), or placebo for one mg once weekly), or placebo for one year,year,

• LS BMD increased by LS BMD increased by 3.0 to 6.7 percent3.0 to 6.7 percent with with denosumabdenosumab and and 4.6 percent with 4.6 percent with alendronatealendronate while it while it decreased by 0.8 decreased by 0.8 percentpercent in the placebo group. in the placebo group.

• Bone density at the total hip increased by 1.9 to 3.6 percent with denosumab and 2.1 percent with alendronate, with a decrease of 0.6 percent with placebo

• After 24 months, reductions in bone turnover markers were sustained with most denosumab doses and with alendronate.

• In a two-year trial of 332 postmenopausal women with osteopenia received denosumab (60 mg administered subcutaneously every six months) or placebo

• Denosumab improved BMD at the LS, Denosumab improved BMD at the LS, total hip, and radius compared with total hip, and radius compared with placebo (6.5 versus -0.6, 3.4 versus -placebo (6.5 versus -0.6, 3.4 versus -1.1, and 1.4 versus -2.1 percent, 1.1, and 1.4 versus -2.1 percent, respectively). respectively).

• Discontinuation of denosumab for 24 months resulted in decreases in LS and total hip BMD comparable to the gains previously achieved during 24 months of therapy.

• Eventos adversos:Eventos adversos:

• There were a greater number of There were a greater number of infections requiring hospitalization in infections requiring hospitalization in the denosumab group the denosumab group (diverticulitis, (diverticulitis, pneumonia, atypical pneumonia, pneumonia, atypical pneumonia, appendicitis, cellulitis, and appendicitis, cellulitis, and labyrinthitis)labyrinthitis) in some trials, but not in in some trials, but not in othersothers

• Overall rates of adverse events of Overall rates of adverse events of neoplasm were similar neoplasm were similar

• A longer and larger (more than 7700 A longer and larger (more than 7700 postmenopausal women) phase III postmenopausal women) phase III trial was completed in 2008; safety trial was completed in 2008; safety and fracture prevention data are and fracture prevention data are forthcoming.forthcoming.

Emerging therapiesEmerging therapies   

• Oral calcium sensing receptor Oral calcium sensing receptor antagonistsantagonists — Administration leads to — Administration leads to a transient rise in endogenous a transient rise in endogenous parathyroid hormone, similar to parathyroid hormone, similar to intermittently administered exogenous intermittently administered exogenous parathyroid hormone parathyroid hormone

• Sclerostin inhibitorsSclerostin inhibitors — Sclerostin is — Sclerostin is produced by osteocytes and inhibits produced by osteocytes and inhibits bone formationbone formation. .

• In animal models, administration of In animal models, administration of sclerostin antibodies sclerostin antibodies increases bone increases bone massmass, and sclerostin knock-out mice , and sclerostin knock-out mice have have increased bone formation and increased bone formation and high bone masshigh bone mass

• Integrin antagonistsIntegrin antagonists — Integrins — Integrins mediate the adhesion of osteoclasts to mediate the adhesion of osteoclasts to the bone surface, an important initial the bone surface, an important initial step for bone resorption step for bone resorption