1. Tratamento da Osteoporose Mulheres na pós menopausa
Paula Miguel Lara
-Reumatologia-

2. Use of selective estrogen receptor modulators in postmenopausal women
The role of postmenopausal hormone therapy for prevention of chronic disease has been greatly diminished
that estrogen-progestin therapy is associated with an increased risk for breast cancer, coronary disease, stroke, and venous tromboembolism

3. Synthetic estrogen receptor (ER) ligands such as raloxifene and tamoxifen represent an alternative for women suffering from menopausal symptoms.
Because these drugs bind with high affinity to the ER and possess tissue-selective estrogen agonist and antagonist properties, they are called selective estrogen receptor modulators (SERMs)

4. Raloxifeno
Drugs that have estrogen activity in bone and other systems but not in reproductive tissue.
In ovariectomized animals raloxifene preserves bone density, lowers serum total cholesterol, and inhibits aortic cholesterol accumulation, without causing endometrial hyperplasia

5. 1145 healthy European and North American postmenopausal women, double-blind, placebo-controlled trials with random assignment to receive raloxifene hydrochloride, 30, 60, or 150 mg, or placebo daily
Over two years, BMD increased significantly at all sites tested with each dose of raloxifene, while there was bone 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

6. (LDL) cholesterol decreased significantly in each of the raloxifene groups compared with placebo
total cholesterol decreased by 6.4 percent versus 1.2 percent for placebo, while serum LDL cholesterol decreased by 10.1 versus 1.0 percent (diminui ICO)
There was also no difference in endometrial thickness, or in complaints of breast pain or vaginal bleeding

7. Hot flushes occurred more often in the raloxifene-treated patients (25 percent) than in the placebo-treated patients (18 percent).
This was the only significant side effect of raloxifene detected.
Study 6828 of the women receiving 60 mg and 120 mg raloxifene, 6.6 and 5.4 percent, respectively, had new vertebral fractures, compared with 10.1 percent in the placebo group;

8. the risk of nonvertebral fractures was similar in the three groups
Raloxifene did not increase the risk of endometrial cancer.
But it did increase the incidence of thromboembolic disease (TVP e AVC fatal), hot flashes, influenza-like symptoms, peripheral edema, and leg cramps

9. Potência:
Raloxifene appears to be a less potent antiresorptive agent than alendronate or estrogen
In a one-year study of 331 postmenopausal women with osteoporosis, alendronate (10 mg/day) increased BMD more than raloxifene (60 mg/day)

10. Quando usar:
Reserve the use of this drug for patients who cannot tolerate alendronate and/or risedronate
Do not recommend raloxifene as the first line drug because it has less antiresorptive action than the bisphosphonates
Eventos adversos

11. Parathyroid hormone therapy for osteoporosis
PTH is an 84-amino acid polypeptide secreted by the parathyroid glands in response to relatively small changes in serum calcium
(PTH1r) membrane surface receptor expressed in multiple tissues including cartilage, bone, breast and kidney
Is one of the two major hormones modulating calcium and phosphate homeostasis, the other being calcitriol

12. Its actions to stimulate renal tubular calcium reabsorption and bone resorption.
Chronic exposure to high serum PTH concentrations (as seen with primary or secondary hyperparathyroidism) results in bone resorption.
Intermittent administration of recombinant human PTH has been shown to stimulate bone formation more than resorption, at least over the first 12 months of treatment.

13. MECHANISMS OF ACTION
PTH 1-34 (teriparatide, Forteo) "anabolic" agents stimulate bone formation, activate bone remodeling and are administered subcutaneously as daily injections 20mcg/day for the treatment of severe osteoporosis
PTH stimulates preosteoblasts to mature into bone-forming osteoblasts that lay down collagen and mineralize matrix

14. Bone formation begins within the first month of PTH treatment and peaks six to nine months after initiation of daily PTH
Markers of bone turnover indicate that bone resorption in patients on PTH begins peaks after 12 months of treatment
Most of the gains in BMD occur in the first few months, although antifracture efficacy is evident only after six months or more of treatment

15. The effects of PTH are dose-dependent, such that higher daily doses result in greater increases in formation, and subsequently higher BMD with treatment
Intermittent PTH treatment enhances trabecular more than cortical bone mass
Qualitative changes in trabecular micro architecture
The improvement in the mechanical strength of the skeleton and its resistance to fracture

16. 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 group, when compared to placebo, BMD increased by 9 and 3 more percentage points in the lumbar spine and femoral neck.
40 mcg group, when compared to placebo, BMD increased by 13 and 6 more percentage points in the lumbar spine and femoral neck

17. The main adverse effects of PTH were nausea, headache, and hypercalcemia, occurring more commonly at the higher dose.
Fracture Prevention Trial (FPT), 1600 women with prior vertebral fractures receiving PTH 1-34 (20 mcg or 40 mcg/day) or placebo, there was significant vertebral and non-vertebral fracture efficacy

18. Fracture risk reduction did not differ by dose, even though BMD changes were significantly greater with 40 mcg/day
The Fracture Prevention Trial, PTH administration decreased vertebral fracture rates by 65 to 75 percent
The percentage of vertebral fracture reduction that could be attributed to the improvement in spine BMD was only 30 to 40 percent

19. Non-BMD determinants of bone strength:bone geometry, microarchitecture, remodeling rate, damage accumulation, and/or collagen/mineral matrix properties
COMBINATION THERAPY
PTH plus bisphosphonate therapy - no additional benefit for spine or hip BMD compared with PTH alone  

20. In patients who are taking raloxifene but require additional therapy, it is unclear whether teriparatide should be added to or replace raloxifene.
Up to date do not recommend combination therapy with raloxifene and teriparatide.
Fracture Prevention Trial after discontinuation of teriparatide were followed for an additional 18 months in an open label extension.

21. 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 alendronate during that year following PTH, preserved the increase of 30 percent in trabecular BMD gained in the first year by PTH

22. Potential candidates for PTH therapy include
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 unable to tolerate bisphosphonates or who have relative contraindications to bisphosphonates (achalasia, scleroderma esophagus, esophageal strictures).

23. Fail other osteoporosis therapies
Not used as a first-line drug for treatment or prevention of osteoporosis.
ADVERSE EVENTS
Hypercalcemia and hypercalciuria are the two most common side effects of both
Only 3 percent had persistent hypercalcemia requiring dose reduction

24. Hypercalcemia was more common with the 40 mcg dose (which is not 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
Nausea and headache; muscle cramps

25. Serum uric acid increases; an attack of gout
Of more than 300,000 patients worldwide treated with Forteo, there has been one reported case of osteosarcoma in a postmenopausal women taking Forteo
Study in rats, osteosarcoma occurred in higher doses and long duration

26. Pretreatment evaluation
Serum Ca, P, creatinine, alkaline phosphatase, albumin, 25-hydroxyvitamin D, uric acid
24-hour urine Ca, creatinine
vitamin D deficient should be replaced with vitamin D prior to starting PTH therapy
uric acid pre-treatment

27. Precautions
Primary or secondary hyperparathyroidism should not receive PTH
Patients who are at increased baseline risk for osteosarcoma, such as those with Paget disease of bone, history of prior radiation therapy
Pre-existing malignancies, renal stones, gout, or renal insufficiency

28. Strontium ranelate Inhibit bone resorption and increase bone formation
Two-year clinical trial of 353 postmenopausal women with osteoporosis and at least one vertebral fracture who were randomly assigned to receive strontium ranelate or placebo
lumbar spine mineral density increased in a dose-dependent manner (maximum effect was with the highest dose used, 2 g/day)

29. In the second year of the study, the risk of new vertebral fractures decreased in the 2 g/day group.
1649 postmenopausal women with osteoporosis and at least one vertebral fracture were randomly assigned to receive strontium ranelate (2 gm/day) or placebo for three years
New vertebral fractures was decreased significantly by 41 percent during the three-year study period

30. Bone mineral density at the LS, increased by 8 percent compared with the placebo group.
A meta-analysis of four trials - evidence that strontium ranelate is effective for reducing the risk of vertebral fractures, and to a lesser extent, non-vertebral fractures
Effective and well-tolerated therapy.

31. Denosumab 
RANKL, a member of the TNF superfamily, is essential for the function of bone-resorbing osteoclasts;
RANKL accelerates osteoclastogenesis when it binds to its receptor, RANK, but is blocked by osteoprotegerin, which is produced by osteoblasts
Denosumab is a humanized monoclonal antibody against RANKL that reduces osteoclastogenesis

32. A phase 2 trial of 412 postmenopausal women receive denosumab (at a dose of 14, 60, 100, or 210 mg subcutaneously every three or six months), open-label alendronate (70 mg once weekly), or placebo for one year,
LS BMD increased by 3.0 to 6.7 percent with denosumab and 4.6 percent with alendronate while it decreased by 0.8 percent in the placebo group.

33. Bone density at the total hip increased by 1. 9 to 3
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

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

35. Eventos adversos:
There were a greater number of infections requiring hospitalization in the denosumab group (diverticulitis, pneumonia, atypical pneumonia, appendicitis, cellulitis, and labyrinthitis) in some trials, but not in others
Overall rates of adverse events of neoplasm were similar

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

37. Emerging therapies 
Oral calcium sensing receptor antagonists — Administration leads to a transient rise in endogenous parathyroid hormone, similar to intermittently administered exogenous parathyroid hormone
Sclerostin inhibitors — Sclerostin is produced by osteocytes and inhibits bone formation.

38. In animal models, administration of sclerostin antibodies increases bone mass, and sclerostin knock-out mice have increased bone formation and high bone mass
Integrin antagonists — Integrins mediate the adhesion of osteoclasts to the bone surface, an important initial step for bone resorption