1、Advances in osteoporosis,-New findings regarding the pathophysiology of osteoporosis.-Identifying who needs to be treated.-Current treatment guidelines.-Monitoring therapy.-Areas of future development.,Objectives:,Impact of osteoporosis,In 2002 NOF(National Osteoporosis Foundation)published the proj
2、ected prevalence of those aged 50 and older based on yr 2000 census3: 2002 2010 2020Women with osteoporosis: 7.8 9.1 10.5Women with low bone mass: 21.8 26 30.4Men with osteoporosis: 2.3 2.8 3.3Men with low bone mass: 11.8 14.4 17.1 (number in millions),Epidemiology:,Osteoporosis fracture incidence,I
3、ncidence and Economic Burden of Osteoporosis-Related Fractures in the United States, 20052025.RusselBurge, BessDawson Hughes,DanielHSolomon,JohnBWong,AlisonKing,AnnaTosteson.,Projected annual direct costs of osteoporosis $25.3billion by 202541Osteoporotic fractures accounted for:17 billion in direct
4、 medical costs. 41400,000 hospital admissions.422.5million physician visits. 42180,000 nursing home admissions42,Cost of osteoporosis,Pathogenesis of osteoporosis,Bone is comprised of 2 components:40% organic collagenous 60% inorganic (mineral)matrix providing tensile mostly in the form ofstrength.
5、Calcium hydroxyapetite providing compressive strength.,Bone Architecture,Metabolic bone disease categorized by histology :Osteoporosis OsteomalaciaDecrease in matrix Bone matrix intactand mineral. reduced mineral.Osteoporosis defintion by NIH Consensus Conference, 2000: Skeletal disorder characteriz
6、ed by compromised bone strength predisposing to an increased risk of fracture. Bone strength= Bone density + Bone quality1,Definition:,Regulation of bone remodeling.,Canalis E et al. N Engl J Med 2007;357:905-916,Signals that determine the differentiation, function, and death of these cells and thei
7、r progenitors determine how many units are activated over time, how active and well-balanced the basic multicellular unit is, and whether, at the end of the cycle, bone mass will be gained, lost, or stable4,Local growth factors that regulate bone formation,Canalis E et al. N Engl J Med 2007;357:905-
8、916,Bone morphogenetic proteins : members of TGF beta superfamily of polypeptides, which includes activins and inhibins.5 These proteins bind to and activate specific receptors to initiate signal transduction and influence intracellular events leading to osteoblastogenesis 6, 7,Wnt :uses a Wnt beta-
9、catenin signaling pathway.8 Wnt binds to specific receptors, and to low-density lipoprotein receptorrelated proteins 5 and 6 (LRP5 and LRP6). This stabilizes the beta-catenin which translocates into the nucleus and regulates gene expression.,IGF-I: made in the liver and other tissues, including the
10、skeleton, mediates the effects of growth hormone on longitudinal bone growth.9 IGF-I exerts direct actions in bone and is necessary for skeletal development and the maintenance of bone mass.9 It acts both as a circulating growth hormonedependent hormone and as a local skeletal growth factor influenc
11、ed by PTH.10,11,12 IGF-I primarily influences the differentiated function of the osteoblast and prevents osteoblast apoptosis,PTH-related protein: produced by bone and cartilage cells has developmental and local regulatory function.13,14 Its secretion by lactating mammary glands may play a role in t
12、he increased rate of bone resorption and rapid bone loss that occurs in lactating women.15Fibroblast growth factor: produced by bone and connective tissue. Regulated by PTH, prostaglandin E2, TGF-beta. It decreases collagen synthesis in vitro but can stimulate bone formation in vivo. 16,17,Local gro
13、wth factors continued:,Local cytokines and prostaglandins,Uptodate: Pathogenesis of osteoporosis 18,Whyte M. N Engl J Med 2006;354:860-863,RANKL: a member of the TNF superfamily of ligands and receptors, is essential for the differentiation, activation, and survival of bone-resorbing osteoclasts.19
14、It is expressed on the surface of marrow stromal cells, activated T cells, and precursors of bone-forming osteoblasts . 19 RANKL accelerates osteoclastogenesis when it binds to its receptor, RANK, on osteoclast precursor cells to enhance nuclear factor- B and other signaling pathways.19 Osteoprotege
15、rin that is produced by osteoblasts, the key modulator of RANKL, acts as a soluble decoy receptor for RANKL and blocks its effects,Parathyroid hormone-is the most important regulator of calcium homeostasis. It maintains serum calcium concentrations by: Stimulating bone resorption Increasing renal tu
16、bular calcium reabsorption Increasing renal calcitriol production. PTH stimulates bone formation when given intermittently, but inhibits collagen synthesis at high concentrations 26,27. It stimulates osteoclast mediated bone resorption when given (or secreted) continuously. It also stimulates gene e
17、xpression and increases the production of several local factors, including IL-6, IGF-1 and an IGF-binding protein, IGF-BP-5, and prostaglandins. 28,37.,Systemic hormones involved:,Canalis E et al. N Engl J Med 2007;357:905-916,Calcitriol: increases intestinal calcium and phosphorus absorption, there
18、by promoting bone mineralization. At high concentrations, under conditions of calcium and phosphate deficiency, it also stimulates bone resorption, thereby helping to maintain the supply of these ions to other tissues. Calcitonin:inhibits osteoclasts and therefore bone resorption in pharmacologic do
19、ses. However, its physiologic role is minimal in the adult skeleton. Its effects are transient, probably because of receptor downregulation.Growth hormone and IGFs:The GH/IGF-1 system and IGF-2 are important for skeletal growth, especially growth at the cartilaginous end plates and endochondral bone
20、 formation.,Glucocorticoids:Have both stimulatory and inhibitory effects on bone cells. Essential for differentiation of osteoblasts and sensitize bone cells to regulators of bone remodeling. Inhibition of bone formation is the major cause of glucocorticoid-induced osteoporosis and may be due to acc
21、elerated apoptosis of osteoblasts and osteocytes 38Thyroid hormones:stimulate both bone resorption and formation. Thus, bone turnover is increased in hyperthyroidism, and bone loss can occur. 39Estrogen and Androgen: reduces rate of bone loss by many local effects like:Reducing the number and depth
22、of resorption cavities.44Promoting osteoclast apoptosis.40Increasing TGF-beta release from osteoblastsInhibiting release of TNF-alpha,Osteoporotic bone showing loss of bone with larger spaces decreasing its strength .2,Diagnosis and evaluation,Is based onClinical risk factorsBMD measurement.Using th
23、e above data a FRAX score can be calculated.,Fracture risk assessment:,Clinical risk factors:,Ebeling P. N Engl J Med 2008;358:1474-1482,Identifying who needs imaging:,Raisz L. N Engl J Med 2005;353:164-171,Raisz L. N Engl J Med 2005;353:164-171,BMD measurement:,Dual-Energy X-Ray Absorptiometry:Resu
24、lts expressed as T-SCORE is the number of SD the measurement is above or below the YOUNG-NORMAL MEAN BMD. Z-SCORE is the number of SD the measurement is above or below the AGE-MATCHED MEAN BMD. Sites used for measurement per WHO criteria:Total proximal femurFemoral neckLumbar spine33percent(1/3rd)ra
25、dius if e/o OA or surgery at other 3 sites.Peripheral skeletal sites predict global # risk, however not used in WHO/FRAX criteria therefore limited value. Changes to therapy at these sites are slow.,WHO diagnostic categories of BMD,Ebeling P. N Engl J Med 2008;358:1474-1482,Quantitative ultrasonogra
26、phy (QUS) does not measure BMD, but instead measures the transmission of ultrasound through accessible limb bones or the reflectance of the ultrasound waves from the bone surface. Quantitative computed tomography (QCT): measures volumetric BMD (vBMD) in mg/cm3, most often at the spine. Unlike DXA, Q
27、CT can isolate trabecular bone from its envelope of cortical bone. The studies are split regarding its superiority to DXA.Emerging technologies:High resolution microCT and microMRI allow noninvasive three-dimensional evaluation of bone microarchitecture. These techniques are used primarily in resear
28、ch settings.,Other imaging techniques:,In 2008, a WHO task force introduced a Fracture Risk Assessment Tool (FRAX), which estimates the 10-year probability of hip fracture or major osteoporotic fractures combined (hip, spine, shoulder, or wrist) for an untreated patient using femoral neck T-score or
29、 Z-score and easily obtainable clinical risk factors for fracture 50.FRAX is based upon data collected from large prospective observational studies of men and women of different ethnicities and from different world regions in which clinical risk factors, BMD, and fractures were evaluated 51,52 . FRA
30、X has been validated in 11 independent cohorts, mainly comprised of women 53. The statistical power of this large dataset allows estimation of fracture probability from an individuals set of risk factors.The country-specific FRAX prediction algorithm is available online at (http:/www.shef.ac.uk/FRAX
31、/). 54In the United States, cost-effectiveness modeling suggests that the 10-year hip fracture probability at which treatment becomes cost-effective (intervention threshold) ranges from 2.5 to 4.7 percent for women and from 2.4 to 4.9 percent in men, depending upon age and assuming annual treatment
32、costs of $600 and a willingness-to-pay threshold of $60,000 . 55,FRAX score,Uses: They can give some indication about the future risk for bone loss and fractures. Useful in monitoring the efficacy of antiresorptive therapy in patients with osteoporosisMarkers indicating rate of bone formation:Serum
33、bone-specific ALP reflects the cellular activity of osteoblasts 56,57,58Serum osteocalcin reflects its rate of synthesis by osteoblasts. Serum concentration of the carboxy-terminal and amino terminal propeptides of type I collagen (PICP and PINP, respectively) reflects changes in synthesis of new co
34、llagen. 59 Markers indicating rate of bone resorption:Serum skeletal acid phosphatase .Urinary excretion of collagen crosslinks deoxypyridinoline (DPD) and the peptide-bound alpha-1 to alpha-2 N-telopeptide crosslinks (NTX), and the c-telopeptide crosslink (CTX) reflects bone resorption and not diet
35、ary intake. 60,Markers of Bone turnover,Initial laboratory tests :Complete chemistry profile (including alkaline phosphatase) CBCCalcium, phosphorus 25 hydroxyvitamin D Urinary calcium excretion Additional laboratory tests if indicated(clinical features/ low Z-score) 24 hour urine for free cortisol
36、Estradiol, FSH, LH, Prolactin , TSHMagnesium 1,25 dihydroxyvitamin D ,Intact PTH Celiac screen SPEP/UPEPESR, Rheumatoid FactorSerum tryptase and histamine levels Homocysteine Skin biopsy for connective tissue disorders COL1A genetic testing for osteogenesis imperfecta Serum and urine markers of bone
37、 turnover,Other lab tests:,Management of osteoporosis,National Osteoporosis Foundation guidelines for pharmacologic intervention in postmenopausal women and men 50 years of age,Guidelines by other organizations:,Rosen C. N Engl J Med 2005;353:595-603,Non-pharmacological therapy,Ebeling P. N Engl J M
38、ed 2008;358:1474-1482,Approved pharmacological therapies,Rosen C. N Engl J Med 2005;353:595-603,Antiresorptive agents: Zoledronic acid 5 mg administered intravenously once yearly.Calcitriol: effective in preventing glucocorticoid-induced and posttransplant-related bone loss.Strontium ranelate:is an
39、orally active drug consisting of two atoms of stable strontium and an organic moiety (ranelic acid). In animal studies, strontium appears to inhibit bone resorption and increase bone formation . Its mechanism of action in humans is less certain. Approved for use in Europe only.Anabolic agentsDenosum
40、abinvestigational humanized monoclonal antibody against RANKL . Encouraging Phase 2 trial results.Tibolonea synthetic steroid whose metabolites have estrogenic, androgenic, and progestagenic properties used in some countries.,Other therapies:,ISCD: recommends follow-up BMD testing (DXA spine and hip
41、) when the expected change in BMD equals or exceeds the least significant change (LSC), which is typically one year after initiation or change of therapy, with longer intervals once therapeutic effect is established. In conditions associated with rapid bone loss, such as glucocorticoid therapy, test
42、ing more frequently is appropriate 43AACE:recommends annual DXA of the LS and proximal femur until stability is achieved, and every two years thereafter. 44NAMS:recommends DXA of the total hip every two years. 45Others:Conservative approach - takes the position that monitoring for efficacy of antire
43、sorptive therapy is unnecessary, as only a minority of patients continue to lose bone on therapy. 46,47,48Bone turnover markers- if DXA cannot be performed at one year then measure fasting urinary NTX or serum CTX before and three to six months after starting antiresorptive therapy. 48,49 If the mar
44、ker has fallen significantly (by 50 percent), the patient can be reassured that the next BMD measurement will likely be stable or improved . Repeat DXA can be done in 2 yrs.,Monitoring therapy:,12/15-lipoxygenase inhibitors: coded by the Alox15 gene which is up regulated in IL4 mediated bone resorpt
45、ion.20Oral calcium sensing receptor antagonists : Administration leads to a transient rise in endogenous parathyroid hormone, similar to intermittently administered exogenous parathyroid hormone 21 Sclerostin inhibitors :Sclerostin is produced by osteocytes and inhibits bone formation 22. Antagonism
46、 of sclerostin might be associated with anabolic effects on bone. Monoclonal antibodies against sclerostin, for example, prevent its binding to Wnt coreceptors, enhancing Wnt signaling and increasing bone mass in rodents and nonhuman primates.23Integrin antagonists : Integrins mediate the adhesion o
47、f osteoclasts to the bone surface, an important initial step for bone resorption 24Cathepsin-K inhibitors Cathepsin K is a protease that may play a role in osteoclast-mediated bone resorption .25,Emerging Therapies:,Antagonists of Dkk-1 : Mutations of LRP5 and LRP6 (wnt coreceptor) that lead to impa
48、ired binding of Dkk-1 are associated with increased bone mass.29 . Dkk-1 antibodies increased BMD, trabecular bone volume, and bone formation in rodents, suggesting that Dkk-1 inhibitors targeted specifically to bone might have potential as an anabolic approach in the treatment of osteoporosis.30Sol
49、uble Activin Receptors : Activin enhances osteoclastogenesis, and its effects on bone formation are controversial.31,32 A soluble activin receptor II, which binds activin and possibly bone morphogenetic protein 3, decreases bone resorption and enhances bone formation in rodents.33,34The Osteoblast P
50、roteasome and Its Inhibitors : Inhibitors of proteolytic processing systems might unmask or enhance anabolic pathways.35,36 The use of proteasome inhibitors will depend on their skeletal specificity and their safety profile, since such inhibitors can induce cellular toxic effects and the intracellular accumulation of misfolded proteins.35,
