Reduction in bone mass has long dominated the thinking about and approach to the problem of osteoporosis. A now large body of evidence indicates that bone mass is not adequate to explain satisfactorily either the skeletal fragility of osteoporosis or the effects of bone active agents. By contrast, bone remodeling activity seems to provide a better explanation of both. Current theory in the field is shifting to this conclusion. This figure represents a revision of the commonly held hierarchical relationship of factors contributing to osteoporotic fracture risk. It shows an enhanced role for bone remodeling in skeletal fragility and also indicates secondary effects of factors such as nutrition and hormones on bone mass.
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.
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.
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.
In the 3D analyses compared with placebo, Teriparatide (TPDT) significantly increased cancellous connectivity density and significantly increased cortical bone thickness & bone volume 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 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.
Update on Osteoporosis
Start treatment for Osteoporosis after Fracture . . . . Teriparatide ( ? ) Sushrut Hosp, Research Centre & Post-Graduate Institute of Orthopedics, Nagpur, India. www . sushrut . org [email_address]
Is treating Osteoporosis a fashion ? What is the most fashionable drug of choice ? By the way whats the real Science ? Questions that arise in mind….
Lets listen to this guy what he has to say….. Sushrut Babhulkar MS Orth, MCh Liverpool England
Projected number of osteoporotic hip fractures worldwide Adapted from Cooper C et al, Osteoporosis Int, 1992;2:285-289 Estimated no of hip fractures: (1000s) 742 378 Total number of hip fractures: 1950 = 1.66 million 2050 = 6.26 million Projected to reach 3.250 million in Asia by 2050 1950 2050 600 3250 1950 2050 668 400 1950 2050 1950 2050 100 629
All fractures are associated with morbidity ! ! ! Cooper C, Am J Med, 1997;103(2A):12S-17S 40% Unable to walk independently 30% Permanent disability 20% Death within one year 80% One year after an hip fracture: Patients (%) Unable to carry out at least one independent activity of daily living
Survival after hip fracture Trombetti A et al, Osteoporos Int, 2002;13:731-737 Expected survival in the general population 2 4 6 8 10 0.00 0.25 0.50 0.75 1.00 Survival probability Time after hip fracture (years) 0 Hip fractured Women Hip fractured Men Women Men
Fracture Bone Strength Material Properties Remodeling Falls Shape & Architecture Exercise & Lifestyle Hormones Nutrition Bone Mass Postural Reflexes Soft Tissue Padding Reproduced with permission from Heaney RP. Bone 33:457-465, 2003 Factors Leading to Osteoporotic Fracture: Role of Bone Remodeling 2004
Pathogenesis of osteoporotic fracture Postmenopausal Bone loss Age related bone loss Low peak bone mass FRACTURE = Fall + Low BMD Poor bone quality (architecture) Non skeletal factors (propensity to fall) LOW BONE MASS Other risk factors LOW BMD = PBM or Loss Adapted from Melton LJ & Riggs BL. Osteoporosis: Etiology, Diagnosis and Management Raven Press, 1988, pp155-179
Microarchitectural Changes in Osteoporosis Bone Mass Trab Thickness Trabecular Number Horizontal Struts Connectivity Anisotropy
aBMD (areal) = g/cm 2 vBMD (volumetric) = g/cm 3 Bone Quality Bone Strength and Microarchitecture Geometry/size Turnover/Remodeling Rate Damage Accumulation Degree of Mineralization Properties of the Collagen/mineral Matrix Shifting the Osteoporosis Paradigm Bone Strength NIH Consensus Statement 2000 Sourced from NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95; 2001 Bone Mineral Density Slide Modified: Review: Reviewer Memo: Source: Memo:
Alteration in bone structure in untreated postmenopausal women Dufresne TE et al, Calcif Tissue Int, 2003;73:423-432 Baseline One year after
Hypothetical Effects of Increasing Bone Mineralization Percentage Mineralization Resistance to fracture forces Improved resistance to bending = stiffness Increasing brittleness Normal =65%
The Mechanical Consequences of Mineralization Turner C et al., Osteopor. Int 2002; 13:97. x x x Displacement Force Hyper-mineralized (Ostepetrosis) Optimal Hypo-mineralized (Osteomalacia) Tough but not Stiff Stiff but not Tough
Goal of osteoporosis management: prevention of the first fracture <ul><li>Women who have 1 vertebral fracture have an 11-fold increased risk of ever having another vertebral fracture 1 </li></ul><ul><li>Women with 1or more pre-existing vertebral fractures have an 5.1-fold increased risk of another vertebral fracture within the next year 2 </li></ul><ul><li>Melton et al. Osteoporos Int 1999: 10; 214-21 </li></ul><ul><li>Lindsay et al. JAMA 2001: 285; 320-3 </li></ul>
Management of Osteoporosis Goals of Therapy <ul><li>Prevent first fragility fracture or future fractures if one has already occurred </li></ul><ul><li>Stabilize/increase bone mass </li></ul><ul><li>Relieve symptoms of fractures and/or skeletal deformities </li></ul><ul><li>Improve mobility and functional status </li></ul>
Major bone measurement techniques Dual-energy X-ray Absorptiometry (DXA) Spine, hip, forearm, calcaneus, whole body Quantitative computed Tomography (QCT) Spine, hip, forearm Ultrasound attenuation and velocity Heel, patella, tibia forearm High-resolution p-QCT Forearm, tibia
WHO criteria for osteoporosis in women Kanis JA et al, J Bone Miner Res, 1994;9:1137-1141 T-Score Normal -1 and above Low bone mass -1 to -2.5 Osteoporosis < -2.5 Established osteoporosis < -2.5 and one or more fractures
Therapeutic options for osteoporosis <ul><li>Stimulators of bone formation = anabolic </li></ul><ul><li>( Fluoride) </li></ul><ul><li>ParaThyroid Hormone </li></ul><ul><li>rhPTH(1-34)= teriparatide </li></ul><ul><li>Mixed mechanism of action </li></ul><ul><li>Active Vitamin D metabolites </li></ul><ul><li>Strontium ranelate </li></ul><ul><li>Recommended for all women at risk for osteoporosis </li></ul><ul><li>Calcium and vitamin D </li></ul><ul><li>Inhibitors of bone resorption </li></ul><ul><li>= antiresorptives </li></ul><ul><li>Bisphosphonates </li></ul><ul><ul><li>Alendronate </li></ul></ul><ul><ul><li>Risedronate </li></ul></ul><ul><ul><li>Ibandronate </li></ul></ul><ul><ul><li>Zoledronate </li></ul></ul><ul><li>Calcitonin </li></ul><ul><li>Estrogen ± progestin </li></ul><ul><li>Selective estrogen receptor modulators ( SERMs ) </li></ul><ul><ul><li>Raloxifene </li></ul></ul>
Lower Higher -2.5 BMD (T-score) Bisphosphonates Osteoporosis Therapy Algorithm Postmenopausal Women Raloxifene PTH Calcitonin HRT HRT During Hot Flashes Post Vasomotor Symptoms Pre fracture Post Fracture Risk of Fracture AGE At Risk/Osteopenia Osteoporosis Severe Osteoporosis STAGE
PTH once-daily continuous RANKL OPG osteoclast bone resorption serum Ca ++ osteoblast apoptosis bone lining cells <ul><li>cbfa1 </li></ul><ul><li>BMP </li></ul><ul><li> PPAR </li></ul><ul><li>Wnt </li></ul><ul><li>IGF 1,2 </li></ul><ul><li>amphiregulin </li></ul> osteoblast number/function bone formation bone mass/strength RANKL OPG Slide Modified: Review: 2004 update: J. Alam WPDF#ja200411a Reviewer Memo: Source: Memo:
Effect of Teriparatide on Structural Indices Quantitative analysis-Significant changes Trabecular bone volume Structure model index Connectivity density Cortical thickness Slide Modified: on: 10/22/2002 12:55:04 PM SL11 Rev: 147 Review: Hong Ren 102202 Reviewer Memo: Source:Eriksen ACR 2002 Memo: ACR 2002 P=0.025 P=0.034 P=0.001 P=0.012 Jiang et al. J Bone Miner Res 2003;18(11):1932-1941 Baseline 2004 Post treatment
Effect of Teriparatide on Skeletal Architecture Patient treated with teriparatide 20µg 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%) Slide Modified: on: 10/22/2002 12:55:03 PM SL10 Rev: 147 on: 9/4/2003 8:11:22 AM SL24 Rev: 72 on: 9/25/2003 6:38:58 PM SL1 Rev: 128 Review: Hong Ren 11-19-02 WPDF global kit #LX200308c (Li Xie) 090403 Reviewer Memo: Source: Patient 1124 B3D-MC-GHAC - UCSF – Jiang 2003 Memo: ACR 2002 changed title, references, added new notes 16Jul03 added to history set, modified notes and title 06Aug03 - MR Reviewed - minor changes 21Sep04 - MR Baseline Follow-up Jiang UCSF Data from Jiang, J Bone Min Res 2003;18(11):1932-1941
I have no mental , sentimental, emotional and FINANCIAL connection with Teriparatide This is what it scientifically does