Medical management of osteoporosis

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Medical Management of Osteoporosis

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  • As estimated 23 million American women have either osteoporosis or low bone mass (osteopenia) 1 . Approximately 1.5 million fractures occur each year. The annual incidence of fractures due to osteoporosis exceeds the incidence of stroke, heart attack, and breast cancer combined 1-3 . 1996 and 2015 Osteoporosis Prevalence Figures. State-by-State Report. Washington, DC: National Osteoporosis Foundation; 1997: Executive summary, 1,2,5 1997 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association; 1996:11,14 Cancer Facts and Figures – 1996. Atlanta, GA: American Cancer Society; 1996:11
  • Main point: Osteoporosis is not problem for women only. In fact, males appear to face a higher risk of mortality following a fracture References: 1. America’s Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation . Washington, DC: National Osteoporosis Foundation; 2002:1-2. 2. Campion JM, Maricic MJ. Osteoporosis in Men. Am Fam Phys . 2003;67:1521-1526. 3. Bone Health and Osteoporosis: A Report of the Surgeon General . Rockville, MD: US Department of Health and Human Services. Office of the Surgeon General; 2004:70.
  • Main point: Differences in fracture rates likely due to differences in bone accumulation and geometric development very early in life (puberty and adolescence), menopause-related bone loss in women, and differences in the patterns of bone loss. Reference: Weber TJ, Gold DT. Update on Male Osteoporosis. Adv Stud Med . 2006;6:171-181.
  • What is Osteoporosis? The definition of osteoporosis continues to evolve as we gain a better understanding of the underlying changes in bone and the mechanisms for these changes that lead to the disease. At a National Institutes of Health Consensus Development Conference held in 2000, osteoporosis was defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture, and states that bone strength is a reflection of both bone density and bone quality. 1   These photographs compare the structure of normal versus osteoporotic bone, illustrating the point that osteoporosis is characterized not only by loss of bone mineral density, but is also associated with a decline in bone quality, including architectural abnormalities, trabecular thinning and loss of trabecular connectivity. This microarchitectural deterioration may particularly increase the risk of vertebral fracture, since trabecular bone dominates in the vertebra.   1. NIH Consensus Development Panel. JAMA 2001;285:785-95
  • Risk Factors for Osteoporosis and Fracture Risk factors for osteoporotic fracture include those that influence the risk of falling and response to trauma, those that influence loss of BMD and those that influence skeletal strength independent of BMD. Maternal family history of hip fracture: This focuses on the likely genetic etiological component to osteoporosis.  
  • Marcus R. Normal and abnormal bone remodeling in man. Ann Rev Med 1987;38:129-141.
  • Slide 3 4 Speaker Notes: Over the last few years, many new therapeutic options have become available for the prevention and treatment of osteoporosis. Commo n ly used agents include a variety of estrogen and estrogen - plus - progestin preparations, selective estrogen receptor modulators ( SERMs ) (such as raloxifene), calcitonin, and bisphosphonates (such as etidronate, alendronate, and risedronate). Calcium and vitamin D are recommended for all women at risk for osteoporosis unless there are specific contraindications.
  • This illustrates the mechanical consequences of mineralization. Bone strength can be thought of in two dimensions. First there is the force required to break bone. This is shown on the vertical axis. As bone increases mineral content it becomes more resistant to force. This is good. The second dimension to describe strength is displacement or how much a bone will bend without breaking. Undermineralized bone is soft and this is a bad thing. As you can see on the graph over-mineralized bone becomes stiff and losses its ability to give without breaking under stress and thus becomes brittle. So it seems like many things in nature, too much or too little of a good thing is not good in the end and the best is an optimum balance.
  • Current therapies decrease fracture risk and reduce the loss of bone, but are unable to reconstitute damaged microarchitecture. Many patients continue to fracture or are at high risk for fracture despite current medical therapy. There is a need for new osteoporosis treatments which can improve the structure of osteoporotic bone with the goal of enhanced fracture risk reduction. __________________ Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant, HK, Eriksen EF. Recombinant Human Parathyroid Hormone (1-34) [Teriparatide] improves both cortical and cancellous bone structure. J Bone Min Res 2003; 18(11):1932-1941. Seeman E. Reduced bone formation and increased bone resorption: rational targets for the treatment of osteoporosis. Osteoporos Int. 2003;14 Suppl 3:S2-8.
  • In the Fracture Prevention Trial teriparatide (TPTD) significantly increased bone mineral density at the lumbar spine and proximal femur, and decreased vertebral and nonvertebral fractures in postmenopausal women with osteoporosis (Neer et al. 2001). 2D histomorphometric analyses and 3D direct measurement (Scanco µCT with isotropic resolution of 17 µm) of paired biopsies (placebo=19, TPTD20=18, TPTD40=14) obtained at baseline and after 18  5 months (mean  SD) (range 12-24 months) treatment were performed. TPTD-treated groups were combined for statistical analyses. By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, -24%; p=0.001), In the 2D analyses and compared with placebo, TPTD significant increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, -24%; P=0.001). In the 3D analyses and compared with placebo, TPTD significantly decreased the cancellous structure model index (TPTD, -12%; placebo, 7%; P=0.025), significantly increased cancellous connectivity density (TPTD, 19%; placebo, –14%; p=0.034), and significantly increased cortical bone thickness (TPTD, 22%; placebo, 3%; P=0.012). The Structural Model Index (SMI) is a measure of the degree that cancellous bone shows plate-like (normal) bone or rod-like (deteriorated) bone. The lower the SMI, the more plate-like the bone structure. _________________ Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant, HK, Eriksen EF. Recombinant Human Parathyroid Hormone (1-34) [Teriparatide] improves both cortical and cancellous bone structure. 2003. J Bone Min Res Vol 18. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344(19):1434-1441.
  • After approximately age 65, age becomes a more accurate predictor of fracture risk than BMD. Note: At the same bone mass (BMD), the risk of fracture increases with each age interval.
  • The incidence of all osteoporotic fractures increases with age. Shortly after menopause, the incidence of Colles' (wrist) fracture starts to increase and continues to do so until the age of 65, at which point it begins to plateau . The incidence of hip fracture, however, increases more slowly with age until later life, when it undergoes a steep exponential rise. The incidence of vertebral fracture is difficult to assess, but, in women, it clearly begins to rise shortly after menopause and continues to do so, without reaching a plateau . At all ages, the incidence of fracture is higher in women than in men, the result of accelerated bone loss following menopause . Wasnich RD: Epidemiology of Osteoporosis In “ Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism” MJ Favus, ed. 4 th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:257-259
  • Parathyroid hormone (PTH) is secreted by the parathyroid glands and is an important regulator of blood calcium concentrations. Synthesis and secretion of PTH are stimulated by a decrease in blood calcium. PTH has three actions: 1) Increase the release of calcium from bone, 2) Reduce renal clearance of calcium, and 3) Stimulate the production of 1,25 (OH) 2 D 3. Human parathyroid hormone is a single chain polypeptide with 84 amino acids and a molecular weight of 9425 Da. The N-terminal region, 1-34, shown here in yellow, is biologically active and sufficient for regulation of mineral ion homeostasis. The crystalline structure of hPTH(1-34) is modeled here red, binding to the PTH/PTHrP receptor shown in blue. Residues at the ligand-receptor interface (yellow) form the interface between the C terminus of hPTH(1-34) and the receptor are highlighted. A hydrophobic patch is formed by residues Trp, Leu, and Leu of hPTH(1-34) and Phe and Leu of the receptor. Arg of hPTH(1-34) interacts with Glu and Glu of the receptor, whereas Lys of hPTh(1-34) interacts with Glu of the receptor. __________________ Proceedings of the National Academy of Sciences of the United States of America 1974;71:384-388. Jin L, Briggs SL, Chandrasekhar S, Chirgadze NY, Clawson DK, Schevitz RW, Smiley DL, Tashjian AH, Zhang F. Crystal structure of human parathyroid hormone 1-34 at 0.9-A resolution. J Biol Chem. 2000 Sep 1;275(35):27238-44.
  • The early scientific history of parathyroid hormone is marked by discovery, exploration, and a period of therapeutic use of parathyroid extracts derived from animals to regulate calcium. The different actions of parathyroid hormone (PTH) were not clearly understood, nor were differences between animal and human PTH. Two characteristics of PTH administration were discovered in the 1930s. First, that excessive administration of PTH had a negative, catabolic effect on bone causing bone loss, and second, that very small doses of PTH stimulated osteoblast formation and increased bone apposition. Concerns over the potential adverse effects of PTH on bone lead to the general perception that PTH causes bone loss. Interest in PTH revived in the the 1970s with the synthesis and sequencing of human PTH which freed scientists from using animal extracts. Preclinical studies demonstrated the potential of intermittent administration of PTH as an anabolic agent that stimulates osteoblasts and bone remodeling. Clinical trials showed the effectiveness of PTH in increasing BMD and preventing new fractures. In 2001, Eli Lilly and Company’s FORTEO ® , teriparatide (rDNA origin) 20  g/day PTH(1-34), was approved in the US for the treatment of postmenopausal women with osteoporosis and of men with low bone mineral density.
  • Although a major action of parathyroid hormone (PTH) is to stimulate osteoclastic bone resorption, Rodan and Martin presented compelling evidence that osteogenic cells of the osteoblast lineage are a principal target of PTH. Intermittent treatment with PTH increases osteoblast number and bone formation. Dobnig and Turner proposed that the increase in osteoblast number in mature rats was due to stimulation of bone lining cells on quiescent surfaces to function as osteoblasts. Jilka et al. reported that daily PTH injections in mice increased the life-span of mature osteoblasts by preventing apoptosis, resulting in increased osteoblast number, bone formation rate, and bone mass. __________________ Rodan GA, Martin TJ. Role of osteoblasts in hormonal control of bone resorption: a hypothesis. Calcif Tissue Int 1981;33:349-351. Dobnig H and Turner RT. Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology 1995;136:3632-3638. Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 1999;104:439-444.
  • Effects of hPTH on cancellous bone histomorphometry were evaluated in male rats using short term subcutaneous (SC) treatment, programmed infusions (1 h/day and 2 h/day) and continuous infusion. Osteoblast perimeter was increased significantly in rats treated with hPTH SC and with programmed infusion of the hormone for 1 h/day. Osteoclast perimeter increased significantly with continuous infusion of the hormone. __________________ Adapted from: Dobnig H and Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997;138:4607-4612.
  • The skeletal effects of PTH depend upon the pattern of systemic exposure. Once-daily administration of PTH stimulates new bone formation on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. This effect of PTH leads to a rapid increase in skeletal mass and an increase in bone turnover markers. By increasing new bone formation, PTH improves skeletal microarchitecture, bone mass and bone strength, and thereby reduces the risk of fracture. Numerous factors have been implicated in the bone forming response, but selective down regulation of osteoclast differentiation factor or RANKL and stimulation of osteoprotegerin (OPG) secretion by osteoblasts seems to play a key role. By contrast, continuous excess of endogenous PTH, as occurs in severe hyperparathyroidism, may be detrimental to the skeleton because bone resorption is stimulated more than bone formation (Hock JM 2001). The continuous infusion of PTH(1-38) in rats resulted in the increased expression of RANKL and decreased expression of both OPG and bone-formation-associated genes such as osteoblast specific transcription factor, osteocalcin, bone sialoprotein, and type I collagen. __________________ Dobnig H, Turner RT. Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology 1995; 136(8):3632-3638. Dobnig H, and Turner RT. Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology 1995;136:3632-3638. Hock, JM. Anabolic Actions of PTH in the skeletons of animals. J Musculoskel Neuron Interact 2001; 2:33-47. Jilka RL, Weinstein RS, Bellido T, et al. Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 1999;104:439-444. Kalu DN, Pennock J, Doyle FH, et al. Parathyroid hormone and experimental osteosclerosis. Lancet 1970;1:1363-1366. Ma YL, Cain RL, Halladay DL, et al. Catabolic Effects of continuous human PTH (1-38) in vivo is associated with sustained stimulation of RANKL and inhibition of osteoprotegerin and gene-associated bone formation. Endocrinology 2001; 142:4047-4054 Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41. Podbesek R, Edouard C, Meunier PJ, et al. Effects of two treatment regimes with synthetic human parathyroid hormone fragment on bone formation and the tissue balance of trabecular bone in greyhounds. Endocrinology 1983; 112:1000-1006. Tam CS, Heersche JNM, Murray TM et al. Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: Differential effects of intermittent and continuous administration. Endocrinology 1982;110:506-512.
  • Not all important characteristics of bone strength are indicated in standard DXA measurements. DXA measurements are affected by the size of the bone, and the amount of mineralization present in the bone (and in the surrounding tissues). However, DXA measurements do not reflect the shape of the bone, nor microscopic architectural issues such as number, alignment, and connectivity of trabeculae; quality of the collagen matrix; or amount (and repair) of microscopic damage such as cracks in the trabecular struts _________________ N. B. Watts. Bone quality: getting closer to a definition. J.Bone Miner.Res. 17 (7):1148-1150, 2002. .
  • CONTRASTING EFFECTS OF TERIPARATIDE AND ALENDRONATE ON BONE TURNOVER ASSESSED BY BONE HISTOMORPHOMETRIC PARAMETERS IN WOMEN WITH OSTEOPOROSIS PJ Meunier 1 , ME Arlot 1 , M McClung 2 , J San Martin 3 , G Boivin 1 , DW Donley 3 , F Bandeira 4 , PD Miller 5 , EF Eriksen 3 1 Laboratoire d’Histodynamique Osseuse and INSERM Unit 403, Faculty of Medicine R. Laennec, Lyon, France 2 OR Osteoporosis Center, Portland OR USA 3 Eli Lilly & Company, Indianapolis, IN, USA. 4 Hosp Agam Magal, UnivPe, Recife, PE, BRAZIL 5 CO Center Bone Research, Lakewood, CO USA AIM: We conducted a randomized double-blind study in postmenopausal women with osteoporosis to contrast the effects of teriparatide 20 µg/d (TPTD) and alendronate 10 mg/d (ALN) on bone remodeling as assessed by bone histomorphometry. METHODS: Patients were randomly assigned to receive either TPTD (n=102) or ALN (n=101) for 18 months. Bone biopsies were obtained in separate subsets of patients at 6 (TPTD, n=8; ALN, n=9) and 18 months (TPTD, n=8; ALN, n=7). RESULTS: Histomorphometric indices of bone remodeling were significantly greater with TPTD than with ALN (mean ± SD). In trabecular bone, indices reflecting bone formation and activation frequency were generally greater at 6 vs. 18 months with TPTD, while the same indices remained suppressed at both time points with ALN. In TPTD, the peak in bone formation indices coincided with peak levels for biochemical markers of bone formation. Bone resorption, as reflected by erosion surface, although generally greater in TPTD compared with ALN, did not reach the magnitude of treatment differences attained in formation indices. Resorption remained relatively constant over time in both groups. CONCLUSION: Bone formation was greater at 6 vs. 18 months with TPTD. The values at both time points were significantly greater than that observed with ALN, confirming the opposite mechanism of action of the two treatments. Furthermore, these results reveal the sustained, positive formation-resorption balance achieved by TPTD compared with ALN.   Bone Envelope 6 months [r1] 18 months [r2] Trabecular TPTD ALN TPTD ALN OS/BS 17.26** ± 7.94 6.83 ± 5.17 12.63* ± 6.64 5.29 ± 3.04 ES/BS 3.08 ±2.03 2.17 ±1.35 3.89 ±2.30 2.59 ± 1.28 MS/BS 8.10** ± 4.42 0.22 ± 0.29 4.40** ± 2.90 0.38 ± 0.31 BFR (µm/d) 0.062* ± 0.036 0.002 ± 0.002 0.030* ± 0.022 0.003 ± 0.002 Ac.f (#/yr) 0.99** ± 0.56 0.02 ± 0.03 0.46** ± 0.32 0.04 ± 0.03 Endocortical         ES/BS 5.60* ± 3.83 2.79 ±1.29 5.62 ± 4.58 4.06 ± 3.51 MS/BS 18.73** ± 10.38 0.44 ± 0.95 9.69** ± 6.73 1.02 ± 1.40 BFR (µm/d) 0.098* ± 0.053 0.007 ± 0.008 0.064* ± 0.049 0.009 ±0.007 *P<0.05; **P<0.01 (TPTD vs. ALN)           [r1] DWD 6 month source RMP.B3DO.GHBM.INTRM6(BBS001DD) & RMP.B3DO.GHBM.INTRM6(BBS002DD)   [r2] DWD 18 month source RMP.B3DO.GHBM.FINAL(BBS008DD) & RMP.B3DO.GHBM.FINAL(BBS009DD)
  • CONTRASTING EFFECTS OF TERIPARATIDE AND ALENDRONATE ON BONE TURNOVER ASSESSED BY BONE HISTOMORPHOMETRIC PARAMETERS IN WOMEN WITH OSTEOPOROSIS PJ Meunier 1 , ME Arlot 1 , M McClung 2 , J San Martin 3 , G Boivin 1 , DW Donley 3 , F Bandeira 4 , PD Miller 5 , EF Eriksen 3 1 Laboratoire d’Histodynamique Osseuse and INSERM Unit 403, Faculty of Medicine R. Laennec, Lyon, France 2 OR Osteoporosis Center, Portland OR USA 3 Eli Lilly & Company, Indianapolis, IN, USA. 4 Hosp Agam Magal, UnivPe, Recife, PE, BRAZIL 5 CO Center Bone Research, Lakewood, CO USA AIM: We conducted a randomized double-blind study in postmenopausal women with osteoporosis to contrast the effects of teriparatide 20 µg/d (TPTD) and alendronate 10 mg/d (ALN) on bone remodeling as assessed by bone histomorphometry. METHODS: Patients were randomly assigned to receive either TPTD (n=102) or ALN (n=101) for 18 months. Bone biopsies were obtained in separate subsets of patients at 6 (TPTD, n=8; ALN, n=9) and 18 months (TPTD, n=8; ALN, n=7). RESULTS: Histomorphometric indices of bone remodeling were significantly greater with TPTD than with ALN (mean ± SD). In trabecular bone, indices reflecting bone formation and activation frequency were generally greater at 6 vs. 18 months with TPTD, while the same indices remained suppressed at both time points with ALN. In TPTD, the peak in bone formation indices coincided with peak levels for biochemical markers of bone formation. Bone resorption, as reflected by erosion surface, although generally greater in TPTD compared with ALN, did not reach the magnitude of treatment differences attained in formation indices. Resorption remained relatively constant over time in both groups. CONCLUSION: Bone formation was greater at 6 vs. 18 months with TPTD. The values at both time points were significantly greater than that observed with ALN, confirming the opposite mechanism of action of the two treatments. Furthermore, these results reveal the sustained, positive formation-resorption balance achieved by TPTD compared with ALN.   Bone Envelope 6 months [r1] 18 months [r2] Trabecular TPTD ALN TPTD ALN OS/BS 17.26** ± 7.94 6.83 ± 5.17 12.63* ± 6.64 5.29 ± 3.04 ES/BS 3.08 ±2.03 2.17 ±1.35 3.89 ±2.30 2.59 ± 1.28 MS/BS 8.10** ± 4.42 0.22 ± 0.29 4.40** ± 2.90 0.38 ± 0.31 BFR (µm/d) 0.062* ± 0.036 0.002 ± 0.002 0.030* ± 0.022 0.003 ± 0.002 Ac.f (#/yr) 0.99** ± 0.56 0.02 ± 0.03 0.46** ± 0.32 0.04 ± 0.03 Endocortical         ES/BS 5.60* ± 3.83 2.79 ±1.29 5.62 ± 4.58 4.06 ± 3.51 MS/BS 18.73** ± 10.38 0.44 ± 0.95 9.69** ± 6.73 1.02 ± 1.40 BFR (µm/d) 0.098* ± 0.053 0.007 ± 0.008 0.064* ± 0.049 0.009 ±0.007 *P<0.05; **P<0.01 (TPTD vs. ALN)           [r1] DWD 6 month source RMP.B3DO.GHBM.INTRM6(BBS001DD) & RMP.B3DO.GHBM.INTRM6(BBS002DD)   [r2] DWD 18 month source RMP.B3DO.GHBM.FINAL(BBS008DD) & RMP.B3DO.GHBM.FINAL(BBS009DD)
  • One thousand six hundred thirty-seven postmenopausal women with osteoporosis were enrolled in the teriparatide fracture prevention trial with a median duration of treatment with study drug of 19 months. Patients were randomized to 20  g/day (n=541) or 40   g/day (n=552) of teriparatide plus calcium and vitamin D compared with patients randomized to calcium and vitamin D alone (n=544). To examine the effects of teriparatide on cancellous and cortical bone, iliac crest bone biopsies were taken from a subset of women at baseline. Follow‑up bone biopsies were assessed in half of these patients at Month 12 and in the other half of these patients at Month 24. Treatment duration for these women at the time of the second biopsy was 18  5 months (range, 11–24 months). Biopsies of patients treated with teriparatide showed no osteomalacia or woven bone and did show trends toward increased mineral appositional rate and increased wall thickness. Post-treatment biopsies were taken too late to detect significant teriparatide-induced changes in remodeling activity. Cortical porosity was expressed as the average percent area occupied by Haversian canals within the inner and outer cortical tissue, and was assessed by point counting. No significant increase in cortical porosity was observed in the pooled teriparatide treated group. __________________ Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant, HK, Eriksen EF. Recombinant Human Parathyroid Hormone (1-34) [Teriparatide] improves both cortical and cancellous bone structure. J Bone Min Res 2003; 18(11):1932-1941.
  • Jiang reported improved skeletal architecture by treatment with teriparatide 20  g/day. 3D analysis of iliac crest bone biopsies revealed significant increases in cancellous bone volume and connectivity, increased trabecular bone volume, trabecular connectivity, and cortical thickness and improved trabecular morphology with a shift toward a more plate-like structure. One thousand six hundred thirty-seven postmenopausal women with osteoporosis were enrolled in the teriparatide Fracture Prevention Trial with a median duration of treatment with study drug of 19 months. Patients were randomized to 20  g/day (n=541) or 40 mg/day (n=552) of teriparatide plus calcium and vitamin D compared with patients randomized to calcium and vitamin D alone (n=544). To examine the effects of teriparatide on cancellous and cortical bone, iliac crest bone biopsies were taken from a subset of women at baseline and after 12 to 24 months of treatment. Female, age 65 Duration of therapy: 637 days (approx 21 months) Baseline BMD: Total spine 0.826 gm/cm**2 (T-score = -2.0, nhanes 98) Fem neck 0.547 gm/cm**2 (T-score = -2.6, nhanes 98) Endpoint BMD: Total spine 0.887 gm/cm**2 (+7.4%) (T-score -1.7) Fem neck 0.621 gm/cm**2 (+13.5%) Total Hip: +5.2% (group mean = 2.6 ± 4.9%) __________________ Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant, HK, Eriksen EF. Recombinant Human Parathyroid Hormone (1-34) [Teriparatide] improves both cortical and cancellous bone structure. J Bone Min Res 2003; 18(11):1932-1941.
  • 2D and 3D analyses of biopsies of patients treated with teriparatide overall showed increased biomechanical competence, an effect that reasonably explains why treatment with teriparatide consistently and significantly reduces the incidence of vertebral and nonvertebral fractures. __________________ Jiang Y, Zhao JJ, Mitlak BH, Wang O, Genant, HK, Eriksen EF. Recombinant Human Parathyroid Hormone (1-34) [Teriparatide] improves both cortical and cancellous bone structure. J Bone Min Res 2003; 18(11):1932-1941.
  • In the fracture prevention trial, the overall treatment group difference in adverse events was not statistically significant at the 0.05 level (P=0.098). There was a statistically significant reduction (P=0.047) in the overall incidence of treatment-emergent adverse events in the teriparatide TPTD20/day treatment group, compared with placebo. There were no statistically significant differences or trends among treatment groups in the incidence of dizziness. Dizziness was the most commonly reported adverse event in the nervous system, with 33 (6.1%) patients in the placebo group, 50 (9.2%) patients in the TPTD20 group, and 44 (8.0%) patients in the TPTD40 group reporting dizziness (P=0.144). The frequencies of nausea and headache in the TPTD20 group were similar to placebo, 3% reported leg cramps. Participants reported significantly more nausea and headache in the TPTD40 group than in placebo (P<0.001). Incidences of leg cramps in the TPTD40 group were similar to placebo. One hundred twenty-six (7.7%) patients discontinued the study due to adverse events: 32 (5.9% of 544) in the placebo group, 35 (6.5% of 541) in the teriparatide TPTD20 treatment group, and 59 (10.7% of 552) in the teriparatide TPTD40 treatment group. _________________ Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344(19):1434-1441. Data on file, Eli Lilly and Company
  • In the fracture prevention trial, treatment with teriparatide resulted in transient increases of serum calcium, urinary calcium, and serum uric acid. There was no statistically significant change in the 24-hour postdose serum calcium compared with baseline. There was, however, a significant, dose-dependent, transient increase in the peak postdose serum calcium, which occurred approximately 4 hours after each dose. The majority of patients who experienced at least one elevated postdose serum calcium were identified within the first 3 to 6 months after randomization. Beyond 6 months, the incremental incidence of new postdose hypercalcemia was similar to placebo. Mean 24-hour urinary calcium excretion increased slightly during teriparatide treatment (0.75 mmol/day). Serum uric acid concentrations rose by 13% to 20% for teriparatide treatment 20  g/day and by 20% to 25% for teriparatide treatment 40  g/day with no clinical consequences. __________________ Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344(19):1434-1441. FORTEO USPI (United States Package Insert) 2004
  • In the fracture prevention trial, the overall treatment group difference in adverse events was not statistically significant at the 0.05 level (P=0.098). There was a statistically significant reduction (P=0.047) in the overall incidence of treatment-emergent adverse events in the teriparatide 20-  g/day treatment group, compared with placebo. No major adverse events occurred, no increase in the incidence of cancer, no change in blood pressure or heart rate, and no effect on the incidence of cardiovascular disease. There was no effect on the incidence of life-threatening illnesses or mortality. _________________ Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344(19):1434-1441. Data on file, Eli Lilly and Company
  • ___________________ Ettinger B, San Martin J, Crans G, Pavo I. Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J Bone Miner Res 2004; 19(5):745-751.
  • __________________ Ettinger B, San Martin J, Crans G, Pavo I. Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J Bone Miner Res 2004; 19(5):745-751.
  • The Osteoporosis Continuum This slide illustrates both the anatomy of a normal spine versus a spine with multiple fractured vertebra, as well as its clinical impact on a woman as she ages from 50 to 75 years.   The clinical impact of vertebral fractures occurs with the collapse of one or more vertebra as a result of minimal trauma. Multiple vertebral fractures can cause spinal deformity (thoracic kyphosis or dowager ’ s hump), shortened stature, and chronic disability and pain. Vertebral fractures can ultimately have financial, physical, and psychosocial consequences affecting both the woman and her family.
  • Approximately 4%-28% of the observed fracture risk reduction following treatment with antiresorptive therapies can be predicted from observed changes in BMD: Alendronate 16% (Cummings 2002); Risedronate 7-28% (Li 2001); Raloxifene 4% (Sarkar 2002).
  • Medical management of osteoporosis

    1. 1. Medical Management of Osteoporosis A.Arputha Selvaraj APMP-IIM Calcutta
    2. 2. Annual Incidence of Common Diseases in Women Cases per year 2000000 1500000 1000000 500000 0 Osteoporotic Fractures1 Heart Attack2 1996 and 2015 Osteoporosis Prevalence Figures. State-by-state Report 1997 Heart and Stroke Statistical Update 3 Cancer Facts and Figures - 1996 1 2 Stroke2 Breast Cancer3
    3. 3. Prevalence of Osteoporosis in Men Nearly 1/3 of the 44 million Americans who currently have or are at risk for osteoporosis are men1 14 million men have or are at risk for osteoporosis1 This figure is expected to increase to over 17 million in 2010 and over 20 million in 20201 1 in 4 men over age 50 may have an osteoporotic fracture Male mortality risk after a fracture may exceed that of women2 1. America’s Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation. Washington, DC: National Osteoporosis Foundation; 2002:1-2. 2. Am Fam Phys. 2003;67:1521-1526.
    4. 4. Different Fracture Rates in Men versus Women • Male/female differences in bone accumulation and geometric development during puberty and adolescence give a mechanical advantage to men – Formation of periosteal bone leads to bigger bones – greater diameter and cortical thickness in long bones – Larger vertebral bodies • Accelerated bone loss due to menopause in women • Pattern of trabecular bone loss affects bone strength – With aging, loss of horizontal connectivity in women versus thinning of trabeculae in men Adv Stud Med. 2006;6:171-181.
    5. 5. • men are less likely to fracture than women, the lifetime risk of fracture in men is 13% to 25%. • bone loss in men is more gradual than that observed in women until about age 65. • after age 70-75, bone loss in men is greater than that observed in women of the same age Bilezikian JP. J Clin Endocrinol Metab. 1999;84:3431-3434. De Laet CE, et al. J Bone Miner Res. 1998;13:1587-1593.
    6. 6. Fractures • The main morbidity of osteoporosis • Almost 50% of women will suffer an osteoporotic fracture in their lifetime1 • Previous fractures are strong predictors of future fractures2-4 • Overall: 46% vertebral; 16% hip; 16% wrist5 1. Seeman E. Australian Doctor 2000; 7 April: I-VIII; 2. Ross PD, et al. Ann Intern Med 1991; 114: 919-23; 3. Black DM, et al. J Bone Miner Res 1999; 14: 821-8; 4. Klotzbuecher CM, et al. J Bone Miner Res 2000; 15: 721-39; 5. Access Economics Report for Osteoporosis Australia, 2001
    7. 7. Projected Global Distribution of Fractures 8.8 5.7 0.7 0.6 0.8 2.3 0.2 4.4 Asia 31.2 7.1 Asia 12.5 51.1 20.9 11.9 1990 28.6 Asia Russia Europe Middle East 13 N America Oceania 2050 Latin America Africa
    8. 8. Osteoporosis Definition: 2000’s Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality. NIH Consensus Conference 2000 Normal Bone NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95, 2001 Osteoporosis
    9. 9. Risk Factors for Osteoporosis and Fracture Non-Modifiable • Age • Female Sex • Maternal family history of hip fracture • Low birth weight • Disease predisposing to osteoporosis Potentially Modifiable • History of falls • Body mass index • Drug therapy (e.g. corticosteroid use,etc) • Primary or secondary amenorrhea • Early menopause • Smoking • Alcohol • Dietary calcium and vitamin deficiency Adapted from Jordan & Cooper Best Practise & Res Clin Rheumatol 2002
    10. 10. Pathophysiology -Osteoporosis • Bone remodeling occurs throughout an individual’s lifetime • In normal adults, the activity of osteoclasts (bone resorption) is balanced by that of osteoblasts (bone formation) • With the onset of menopause (mid-forties or fifties), diminishing estrogen levels lead to excessive bone resorption that is not fully compensated by an increase in bone formation
    11. 11. Bone Remodeling A continuous process of skeletal breakdown and renewal that continues throughout life. Remodeling constitutes the fundamental means by which bone is added or subtracted from the adult skeleton. Marcus R. 1987
    12. 12. Microarchitectural Changes in Osteoporosis ↓ Bone Mass ↓ Trab Thickness ↓ Trabecular Number ↓ Horizontal Struts ↓ Connectivity ↑ Anisotropy
    13. 13. Osteoporosis is a disease not a number ! Several factors assist in identifying those at risk age prior fracture BMD falls
    14. 14. Bone Turnover Markers • Bone turnover markers are components of bone matrix or enzymes that are released from cells or matrix during the process of bone remodeling (resorption and formation). • Bone turnover markers reflect but do not regulate bone remodeling dynamics.
    15. 15. Diagnosis of Osteoporosis • Physical Examination • Measurement of Bone Mineral Content Dual X-ray absorptiometry(DXA) Ultrasonic measurement of bone CT Scan Radiography
    16. 16. WHO Criteria for Diagnosis of Bone Status Diagnostic criteria* Classification T is above or equal to -1 Normal T is between -1 and -2.5 mass) Osteopenia (low bone T is -2.5 or lower Osteoporosis T is -2.5 or lower + fragility fracture(s) Severe or established osteoporosis *Measured in "T scores." T score indicates the number of standard deviations below or above the average peak bone mass in young adults.
    17. 17. Therapeutic options for osteoporosis Inhibitors of bone resorption (in alphabetical order) • Bisphosphonates – Alendronate – Etidronate – Risedronate • Calcitonin – Nasal • Estrogen ± progestin • Selective estrogen receptor modulators (SERMs) – Raloxifene Stimulators of bone formation • (Fluoride) • Parathyroid hormone Mixed mechanism of action • Vitamin D and metabolites • Strontium ranelate Recommended for all women at risk for osteoporosis • Calcium and vitamin D
    18. 18. Antiresorptive Agents Increase BMD by Decreasing Remodeling Space and Prolonging Mineral Acquisition High Turnover Older, relatively highly Mineralized bone Antiresorptive Agent Low Turnover Remodeling space Adapted from David Dempster, Ph.D. New relatively undermineralized bone
    19. 19. Hypothetical Effects of Increasing Bone Mineralization Improved resistance to bending = stiffness Resistance to fracture forces Increasing brittleness Percentage Mineralization Normal =65%
    20. 20. The Mechanical Consequences of Mineralization x Hyper-mineralized (Ostepetrosis) Stiff but not Tough x Optimal x Hypo-mineralized (Osteomalacia) Force Tough but not Stiff Displacement Turner C et al., Osteopor. Int 2002; 13:97.
    21. 21. Clinical Need for New Osteoporosis Treatment • Current antiresorptive treatments reduce bone loss and decrease fracture risk • Antiresorptive agents are unable to form new bone or restore microarchitecture • Some patients remain at high risk for fracture after antiresorptive treatment • Teriparatide forms new bone and restores microarchitecture, thus reversing osteoporosis Seeman Osteoporos Int. 2003;14 Suppl 3:S2-8 Jiang et al. J Bone Min Res 2003;18(11):1932-1941 2004
    22. 22. Goal of osteoporosis management: prevention of the first fracture • Women who have 1 vertebral fracture have an 11fold increased risk of ever having another vertebral fracture1 • Women with 1or more pre-existing vertebral fractures have an 5.1-fold increased risk of another vertebral fracture within the next year2 1. 2. Melton et al. Osteoporos Int 1999: 10; 214-21 Lindsay et al. JAMA 2001: 285; 320-3
    23. 23. Management of Osteoporosis Goals of Therapy • Prevent first fragility fracture or future fractures if one has already occurred • Stabilize/increase bone mass • Relieve symptoms of fractures and/or skeletal deformities • Improve mobility and functional status
    24. 24. Role of Exercise in Management of Osteoporosis • Exercise can maintain or increase BMD and improve muscle mass, strength, and balance, decreasing risk of hip fracture • Studies have demonstrated a protective effect of previous physical activity on the risk of hip fracture • Caution when prescribing specific exercises for osteoporotic patients to avoid injury • Exercise programs should be tailored to the individual
    25. 25. Clinical Need for New Osteoporosis Treatment While current treatments reduce fracture risk and allay bone loss, they are unable to restore bone matrix or architecture and many patients remain at high risk for fracture.
    26. 26. Teriparatide improves bone architecture Baseline Patient 1124 B3D-MC-GHAC UCSF Jiang et al Follow-up Female, age 65 Teriparatide 20 µg/day: 637 days (approx 21 mos) BMD Change: ⇒Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) ⇒Total Hip: +5.2% (group mean = 2.6 ± 4.9%)
    27. 27. Structural Indices Quantitative analysis - Significant changes Trabecular bone volume P <0.001 Structure model index P <0.05 Connectivity density P <0.05 Cortical thickness P <0.05 Eriksen ACR 2002 Jiang et al. JBMR 2003, Vol 18.
    28. 28. Age and Bone Mass as Predictors of Fracture Age (Years) Fracture Risk Per 1000 Person–Years 160 80+ 140 120 75-79 100 80 70-74 60 65-69 60-64 55-59 40 50-54 45-49 <45 20 0 >1.0 0.90-0.99 0.80-0.89 0.70-0.79 0.60-0.69 Bone Mass (g/cm2) Hui SL, et al. J Clin Invest. 1988;81:1804-1809. <0.60
    29. 29. Incidence Rates for Vertebral, Wrist and Hip Fractures in Women After Age 50 40 Vertebrae Annual incidence per 1000 women 30 20 10 Hip Wrist 50 Wasnich RD: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th edition, 1999 60 70 Age (Years) 80
    30. 30. Human Parathyroid Hormone 1-34 and 1-84 hPTH (1-34) 1 H2 N -Ser 10 Val Ser Glu Ile Gln Leu Met His Asn Leu 20 Gly Glu Val Arg Glu Met Ser Asn Leu His Lys Arg Lys Lys Leu Gln Asp Val His Asn Phe Trp Leu 30 40 50 60 70 80 - COOH hPTH/PTHrP Receptor hPTH 1-34 Adapted from Proc Natl Acad Sci USA (1974);71:384 Adapted from Jin et al. J Biol Chem (2000);35:27238 (crystal structure)
    31. 31. PTH Paradox Mode and Dose Effect Continuous Infusion Catabolic High Dose Once-daily Administration Low Dose (duration less than 2 h) Anabolic
    32. 32. Intermittent PTH Mechanism of Action PTH binds to cell surface G protein-coupled receptor Activates lining cells. Inhibits apoptosis of osteoblasts Eli Lilly and Company Stimulates differentiation of osteoblasts followed by osteoclasts Net increase in number and activity of osteoblasts, which outpace osteoclast activity
    33. 33. Trabecular Bone Perimeter % Effects of Continuous vs. Intermittent hPTH(1-34) on Osteoblasts and Osteoclasts in Male Rats † Vehicle SC 1 h/day ‡ 2 h/day Continuous * Osteoblast Osteoclast *P<0.05, †P<0.01, ‡P<0.001 vs Vehicle Sourced from Dobnig and Turner, Endocrinology 1997;138:4607-4612
    34. 34. PTH once-daily ↓ osteoblast apoptosis bone lining cells ↑cbfa1 ↑BMP ↑PPARγ ↑Wnt ↑IGF 1,2 ↑amphiregulin continuous ↓ RANKL ↑ OPG ↑ RANKL ↓ OPG ↑ osteoclast ↑ osteoblast number/function ↑ bone resorption ↑ bone formation ↑ serum Ca++ ↑ bone mass/strength Eli Lilly and Company
    35. 35. Theoretical Action of Anabolic vs Antiresorptives on Bone Strength (Mass + Quality) Bone Strength anabolic antiresorptive Time
    36. 36. Bone Strength and Quality DXA is not the Whole Story • Reflected in dual-energy x-ray absorptiometry (DXA) measurements:: – bone size – bone mineral content per unit area – amount of mineralization in bone and surrounding tissues • NOT reflected in DXA measurements: – trabecular connectivity and number – collagen quality – repair of microscopic damage (e.g. microcracks) – bone shape 2004
    37. 37. Summary • After 6 and 18 months, patients treated with teriparatide show significantly higher bone formation activity in cancellous and endocortical bone than patients treated with alendronate. • In the teriparatide group, bone formation and turnover appeared higher at 6 months than at 18 months, corroborating bone marker changes. In the alendronate group, bone formation and turnover remained constantly low. • Bone histomorphometric indices pertaining to bone resorption remained constant throughout the study in both groups. Meunier, et al. Calcif Tissue Int 2004;74(Suppl 1):p. S33
    38. 38. Summary • After 6 and 18 months, patients treated with teriparatide show significantly higher bone formation activity in cancellous and endocortical bone than patients treated with alendronate. • In the teriparatide group, bone formation and turnover appeared higher at 6 months than at 18 months, corroborating bone marker changes. In the alendronate group, bone formation and turnover remained constantly low. • Bone histomorphometric indices pertaining to bone resorption remained constant throughout the study in both groups. Meunier, et al. Calcif Tissue Int 2004;74(Suppl 1):p. S33
    39. 39. Teriparatide has Positive Effects on Bone Histology Paired-Biopsy Study (Treatment Duration 12-24 Months) • No woven bone, mineralization defects, hypercellularity or abnormal architecture. • Significantly increased trabecular bone volume and reduced marrow star volume (vs. placebo). • No increase in cortical porosity in TPTD20 group. In the TPTD40 group, increased porosity at 12 months had resolved by 21 months. Jiang et al. J Bone Min Res 2003;18(11):1932-1941 2004
    40. 40. Effect of Teriparatide on Skeletal Architecture Baseline Patient treated with teriparatide 20µg Data from Jiang, J Bone Min Res 2003;18(11):1932-1941 Follow-up Female, age 65 Duration of therapy: 637 days (approx 21 months) BMD Change: ⇒Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) ⇒Total Hip: +5.2% (group mean = 2.6 ± 4.9%) Jiang UCSF
    41. 41. Teriparatide Has Positive Effects on Bone Structure Summary Jiang et al. J Bone Miner Res. 2003; 18(11):1932-1941 2004
    42. 42. Mechanism of Action Summary Once-daily PTH: • Increases bone remodeling • Stimulates new bone formation on quiescent surfaces • Promotes positive balance at bone remodeling sites Improves: • Bone structure - increases trabecular volume and connectivity - increases cortical thickness • Bone geometry and increases cross-sectional moment of inertia • Bone strength
    43. 43. TERIPARATIDE Effects on Bone Quality Bone Quality Bone Strength 1. 2. 3. 4. 5. 6. and Architecture/Dimensions Turnover Damage Acc. Mineralization Matrix quality Osteocyte apt. Bone Density
    44. 44. Bone Forming and Anabolic Drug- PTH m Riggs and Parfitt, JBMR, 2005, 20: 177-184
    45. 45. Fracture Prevention Trial Adverse Events Placebo (n=544) TPTD20 (n=541) TPTD40 (n=552) N (%) N (%) N (%) Dizziness 33 (6) 50 (9)* 44 (8) Nausea 41 (8) 51 (9) 98 (18)‡ Headache 45 (8) 44 (8) 72 (13) * Leg cramps 6 (1) 17 (3) * 13 (2) 32 (6) 35 (7) 59 (11) † Withdrawn for AE * P<0.05, †P<0.01 , ‡ P<0.001 vs. Placebo Neer et al. N Engl J Med 2001; 344(19):1434-1441
    46. 46. Fracture Prevention Trial Summary of Teriparatide Effects on Serum and Urine Biochemical Tests • Hypercalcemia absent or mild and transient (normal 24 hours after dose) • Mean 24-hour urinary calcium increased 0.75 mmol/day (30 mg/day) • Mean serum uric acid concentrations increased 13-25% (no clinical symptoms) • Changes reversed after withdrawal of teriparatide • No increase in the incidence of nephrolithiasis or impaired renal function Neer et al. N Engl J Med 2001; 344(19):1434-1441 FORTEO USPI (United States Package Insert) 2004
    47. 47. Fracture Prevention Trial Teriparatide Safety Profile • No change in blood pressure or heart rate • No effect on incidence of cardiovascular disease • No effect on incidence of life-threatening illnesses • No increased cancer incidence • No effect on total mortality Neer et al. N Engl J Med 2001; 344(19):1434-1441
    48. 48. AAA Study: Hypothesis Teriparatide Treatment after Antiresorptives • Prior exposure to alendronate would retard the skeletal response to parathyroid hormone while prior exposure to raloxifene would not. Ettinger et al., J Bone Miner Res. 2004;19(5):745-751
    49. 49. AAA Study: Conclusions - 1 Teriparatide Treatment after Antiresorptives • TPTD stimulates bone turnover and increases BMD in both alendronate and raloxifene pretreated patients • Prior raloxifene does not alter TPTD response • Prior alendronate exposure yields: - early delay in bone turnover response - unexpected early BMD changes - dissociated BMD-bone turnover relationships - less BMD increment after 18 months Ettinger et al., J Bone Miner Res. 2004;19(5):745-751
    50. 50. Assessment of Fracture Risk • DXA Risk of fracture=1.5-3.0 with each SD decrease in BMD Low sensitivity Screening is not recommended Quantitative Ultrasound Risk of fracture= 1.5-2.0 with each SD decrease in BMD
    51. 51. Markers of bone turnover Bone formation markers Alkaline Phosphatase Bone Isoenzyme AP Osteocalcin Procollagen propeptides of type I collagen • Bone Resorption Markers Hydroxyproline Pyrridium crosslinked and associated peptides.
    52. 52. Treatment • Calcium and Vitamine D • Hormone replacement Therapy • Selective estrogen receptor modulators(SERM) • Bosphosphonates • Calcitonin • Parathyroid Hormone • Other Treatments • Non-pharmacological Interventions
    53. 53. Calcium Benefits 1.Slower rate of bone loss. 2.Reduction of fracture in some studies. 3Adjunct to other osteoporosis Treatment. Risk 1.Mild GI Upset. 2.Constipation. 3.?Renal Stone.
    54. 54. Calcium Dose 1994 consensus on optimum calcium intake. Adolescent 1200-1500mg/day Adult upto 65yr 1000mg/day Postmenopausal 1500mg/day
    55. 55. Vitamin D • Essential for intestinal absorption of Calcium. • Daily Recommendation:400-800IU/day • ?Decreased risk of fracture in healthy elderly with normal intake and BMD.
    56. 56. HRT • 27%Risk reduction in non-vertebral fracture. • 33%risk reduction in vertebral fracture. Drawbacks 1.Effective only in age<60yr. 2.Nonsustainable effect.
    57. 57. Bisphosphonates Benefits 1.Potent inhibitor of bone resorption. 2.Reduces osteoclast recruitment. 3.Safe. 4.Effective Risk 1.Low oral bioavailablity. 2.Food,Ca,Ir,Coffie,Tea interferes with absorption. 3.GI Discomfort. 4.Rarely oesophagitis.
    58. 58. Calcitonin • • • • • Peptide from Thyroid C-cell. Direct inhibition of osteoclast activity. Less effective in cortical bone. Salmon Calcitonin nasal spray Dose 200IU/Day
    59. 59. Thank you all
    60. 60. Bone Loss Accelerates After Menopause Peak Bone Mass Bone Mass Menopause 0 10 20 30 Byyny and Speroff 1996 40 50 60 Age (years) 70 80
    61. 61. The Osteoporosis Continuum Kyphotic spine Healthy spine 50 Menopausal 55+ Postmenopausal Experiencing vasomotor symptoms At greater risk for vertebral fracture than any other type of fracture 75+ Kyphotic At risk for hip fracture
    62. 62. Fractures • The main morbidity of osteoporosis • Almost 50% of women will suffer an osteoporotic fracture in their lifetime1 • Previous fractures are strong predictors of future fractures2-4 • Overall: 46% vertebral; 16% hip; 16% wrist5 1. Seeman E. Australian Doctor 2000; 7 April: I-VIII; 2. Ross PD, et al. Ann Intern Med 1991; 114: 919-23; 3. Black DM, et al. J Bone Miner Res 1999; 14: 821-8; 4. Klotzbuecher CM, et al. J Bone Miner Res 2000; 15: 721-39; 5. Access Economics Report for Osteoporosis Australia, 2001
    63. 63. Relationship Between BMD and Fracture • Low baseline bone mineral density (BMD) predicts increased risk of subsequent fractures • However, the relationship between changes in BMD with antiresorptive therapy and the reduction in risk of new fractures is not well understood • The magnitude of the increases in BMD with antiresorptive therapies differs greatly, yet the vertebral fracture risk reductions are similar

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