An Introduction to Clinical Osteoporosis

An Introduction to Clinical Osteoporosis
Sundeep Khosla L. Joseph Melton III Stuart H. Ralston Harold Rosen Ian Reid Gordon J. Strewler Nelson Watts

Definition of Osteoporosis
Normal Bone Osteoporotic Bone • A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. • Bone strength reflects the integration of two main features: bone density and bone quality. This definition of osteoporosis emphasizes that the density and quality of bone are distinct properties. Bone density can be quantified; bone quality is not directly quantifiable. Bone quality is determined by the material properties of bone, its microarchitecture, its geometry, and its rate of turnover. Images courtesy of Ralph Müller

Epidemiology of Osteoporosis
L. Joseph Melton III 3

Patterns of Bone Loss Looker, A.C., et al. Osteoporos Int :468-89, with permission from Springer-Verlag.

Incidence/1,000 person-years
Vertebral Fracture Incidence by BMD in Women and Men Women Incidence/1,000 person-years Calcaneus BMD (g/cm2) Men 10 20 30 40 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 The customary areal BMD measurements obtained clinically (see Part 4) correlate strongly with bone strength and predict fracture risk comparably in women and men, although fewer men than women achieve the lowest levels of BMD where fracture risk is greatest. However, this relates partly to the fact that areal BMD overestimates bone mass in those with larger bones (i.e., men, blacks), and larger bones are stronger and more resistant to fracture. There is little difference in actual volumetric BMD (g/cm3) by gender or race. Ross, P.D., et al. , In: Orwoll E, editor. Osteoporosis in Men. San Diego: Academic Press; 1999: , with permission from Elsevier. 5

Age-Related Fractures
Cooper, C. Trends Endocrinol Metab :224-9, with permission from Elsevier.

Hip Fractures by Gender and Race
Hip fractures are less frequent in men and in nonwhite women, although there is considerable variation among studies. Likewise, forearm fractures are much less common in black, Asian and Hispanic women and among men of all races. The lower fracture risk observed in these groups may be due to the fact that their bone density is typically greater (or at least no different) than white women, their risk of falling is lower, and they may not live as long. By contrast, spine fractures are as frequent in Asian women as white women and may be almost as common among white men, although the latter may reflect occupational injuries and trauma as well as osteoporosis. Cummings, S. R. and L. J. Melton. Lancet :1761-7, with permission from Elsevier. 7

Annual Risk of Hip Fractures
Fracture risk is multifactorial, and many clinical risk factors have been identified (Slide 35). Some of them are also determinants of BMD, but others have an independent influence on fracture risk. Thus, hip fracture incidence was 17 times greater among women with five or more clinical risk factors, exclusive of bone density, than those with two risk factors or fewer. However, even the women with five or more risk factors were at higher risk of fracture if their BMD was in the lowest third. It may be possible in the future to combine standard BMD measurements with clinical risk factors to sharpen fracture risk prediction for individual patients. Cummings, S.R., et al. N Engl J Med :767-73, Copyright © 1995 Massachusetts Medical Society. 8

Remaining Lifetime Risk of Fragility Fractures in the Swedish Population
Type of fracture Women Men Hip Distal forearm Vertebrae (clinical) Proximal humerus Any of the above Lifetime risk at age 50 (%) Osteoporotic fractures are very common. During an average lifetime, the risk of a hip fracture from age 50 years onward has been estimated at 21% for women versus 11% for men in Sweden. This is comparable to the combined lifetime risk of breast, ovarian and endometrial cancer in women and of prostate cancer in men. In the United States, the lifetime risk of any one of these three fractures is 40% for white women and 13% for white men, and these figures will rise further as life expectancy continues to increase. Kanis, J. A., et al. Osteoporos Int :669-74, with permission from Springer-Verlag. 9

Pattern of Mortality after Hip Fracture
60 70 80 90 200 400 600 800 1,000 Age (years) Mortality(rate/1000) Fracture at 60 years at 70 years at 80 years Normal population at 90 years Kanis, J. A., et al. Bone :468-73, with permission from Elsevier. Survival is reduced following most osteoporotic fractures. For hip fracture patients, the excess deaths are due less to the fracture itself than to the serious underlying diseases common in this group. Nonetheless, the risk of dying is dramatically increased immediately after a hip fracture occurs and remains somewhat elevated thereafter. Mortality is increased in patients with osteoporosis even before fractures occur. 10

Excess Morbidity Patterns by Fracture Type
Age (years) Vertebral fracture Hip fracture 50 60 70 80 90 Forearm fracture Kanis, J. A. and O. Johnell. J Endocrinol Invest :583-8, with permission. Osteoporotic fractures have other adverse consequences, and there may be a cascade of morbid effects. Thus, many forearm fractures occur soon after menopause and the resulting disability is usually limited, but patients with multiple or severe vertebral deformities are likely to have height loss, postural changes and chronic pain. Patients with spine and forearm fractures are also at increased risk of hip fractures, which typically occur late in life. Hip fractures often result in global disability and the need for nursing home admission; few patients regain their prefracture level of function. 11

Type of service (millions of $)
Expenditures for Osteoporotic Fractures in the United States (2004 dollars) Nursing Fracture type Inpt Outpt home Total Hip 7, , ,104 Forearm Spine ,040 Other sites 3, , ,511 All sites 12,771 1, , ,188 Type of service (millions of $) National estimates from the United States indicate that direct expenditures for osteoporotic fracture care total over $19 billion annually. Two-thirds of the total is consumed by hip fractures. However, the cost of vertebral and distal forearm fractures together exceeds $1.5 billion each year, while all of the other fractures related to osteoporosis cost an additional $5 billion. Moreover, these figures are underestimates since indirect and intangible costs are not included. Adapted from J Bone Miner Res 1997;12:24-35 with permission of the American Society for Bone and Mineral Research for slides as presented by IBMS BoneKEy. 12

Influence of Rising Hip Fracture Incidence on Projected World-Wide Hip Fractures
No change in rates 1% increase worldwide Europe stable, 2% increase elsewhere Europe stable, 3% increase elsewhere 4,493,000 8,162,000 12,335,000 21,310,000 Scenario 2050 fractures 1990 Base Case = 1,255,000 The global increase in population alone could cause the number of hip fractures worldwide to increase from 1.3 million in 1990 to a projected 4.5 million in If, in addition, hip fracture incidence rates increase by 1% annually, the total in the year 2050 will exceed 8 million. Incidence rates appear to have stabilized in Europe and North America but are increasing more rapidly than this in other areas.4 If incidence rates increase by 3% per year in the rest of the world, hip fractures worldwide could total over 21 million in 2050. Gullberg, B., et al. Osteoporos Int :407-13, with permission from Springer-Verlag. 13

Pathophysiology of Osteoporosis
Sundeep Khosla Gordon J Strewler

Model Trauma Low bone mass/ impaired bone quality Inadequate peak bone mass Early menopausal bone loss Decrease in bone mass/bone quality Calcium/ vitamin D deficiency Other factors Fractures The pathophysiology of osteoporosis in the elderly is complex. Peak bone mass may be inadequate (peak bone mass has primarily genetic determinants, as discussed under Genetics of Osteoporosis) and bone mass is lost with age. Age-related bone loss is accelerated by deficiency of calcium or vitamin D, by menopause and other factors. The quality of bone is also impaired during ageing because of changes in the microarchitecture and material qualities of bone. Most osteoporotic fractures occur with trauma to a bone whose strength has been reduced. 15

-- Decrease in bone mass / bone quality -- Trauma Low bone mass/ impaired bone quality Inadequate peak bone mass Early menopausal bone loss Decrease in bone mass/bone quality Calcium/ vitamin D deficiency Other factors Fractures Both bone mass and bone quality contribute to bone strength. The following slides describe changes with bone quality that are associated with aging or osteoporosis. 16

Bone Remodeling is Accelerated in Osteoporosis

Impairments in Bone Mass and Quality in Osteoporosis
Strength of osteoporotic bone is impaired by: • Loss of bone mass • Reduction in bone quality: • Loss of horizontal struts • Loss of connectivity • Conversion of trabecular plates to rods • Resorption pits are “stress concentrators” • Unfavorable geometry Images courtesy of Ralph Müller

Comparison of Microarchitecture in Normal and Osteoporotic Bone
Images courtesy of Ralph Müller

Loss of Horizontal Struts Weakens Bone
According to Euler’s theorem, The buckling load of a strut is inversely proportional to the square of its effective length. The buckling load of the unsupported trabecula on the right is 16 times less than the supported trabecula on the left According to Euler’s theorem, The buckling load of a strut is inversely proportional to the square of its effective length. The buckling load of the unsupported trabecula on the right is 16 times less than the supported trabecula on the left Bell, G. H., et al. Calcif Tissue Res :75-86, notes courtesy of David Dempster, with permission 20

Resorption Cavities are Mechanical Stress Concentrators
The deeper resorption cavities in postmenopausal bone act to concentrate mechanical stress. Bone will tend to fracture at such sites, as will the cane at right. Courtesy of David Dempster

Effect of Bone Geometry on Bone Strength
2.3 1.7 1.0 Axial Strength 8.0 4.0 Bending Strength Cross-sectional area These three cylinders have identical cross-sectional areas. Their bending strength is determined by the distance of their material from the axis. A larger bone (e.g. in a man) is much stronger than a smaller bone with the same mineral content.

-- Inadequate Peak Bone Mass -- Trauma Low bone mass/ impaired bone quality Inadequate peak bone mass Early menopausal bone loss Decrease in bone mass/bone quality Calcium/ vitamin D deficiency Other factors Fractures

Causes of Inadequate Peak Bone Mass
• Genetic factors determining peak bone mass • Inadequate nutrition during growth and development (particularly calcium and protein intake) • Limited physical activity • Diseases (e.g. thyrotoxicosis, Cushing’s) or drugs (e.g., corticosteroids, anticonvulsants) during growth that impair bone mass acquisition

-- Early Menopausal Bone Loss -- Trauma Low bone mass/ impaired bone quality Inadequate peak bone mass Early menopausal bone loss Decrease in bone mass/bone quality Calcium/ vitamin D deficiency Other factors Fractures Menopause accelerates bone loss in women. The following slides present the pathophysiology of menopausal bone loss. 25

Pattern of Involutional Bone Loss
Cortical Bone Cancellous Bone Menopause Women Men 100 90 80 70 60 50 Age, yrs % of Initial BMD Women experience rapid bone loss at the time of menopause that is attributable to estrogen deficiency (see next slide). Cancellous bone is lost preferentially because its remodeling rate is much faster than cortical bone. Menopausal bone loss is superceded by continuing bone loss at a slower rate. Men lose bone mineral continuously without a climacteric like the menopause. If men become deficient in testosterone, they experience hormone-dependent bone loss much as women do. 26

Estrogen Replacement Prevents Bone Loss Due to Estrogen Deficiency
Spinal QCT (Cancellous Bone) Radius BMC (Cortical Bone) ** 5 -5 -10 -15 1 2 Years of treatment Placebo Conjugated Estrogen, 0.625 mg/day * Change from baseline, % *P<0.01 **P<0.001 Treatment post-oophorectomy Genant, H. K., et al. Ann Intern Med : , with permission, Copyright © 1982 American College of Physicians. Loss of ovarian function at menopause is mimicked by oophorectomy. Oophorectomy causes rapid loss of cancellous bone from the spine (left panel). The rate of bone loss is much slower at the radius (right panel), a skeletal site where most bone is cortical. Bone loss at both skeletal sites is prevented by treatment with conjugated equine estrogen, demonstrating that it results from estrogen deficiency. In this study, radial BMD was measured by single photon absorptiometry. Quantitative computed tomography (QCT) was used to identify a region of interest in spinal cancellous bone and measure specifically changes in cancellous bone volume. 27

Mechanisms of Bone Loss at Menopause
The potential pathways by which menopause leads to bone loss. Osteoclastic bone resorption is increased through the loss of estrogen effects on osteoclasts themselves, stromal cells, T cells, ostoblasts and endothelial cells. All of these latter cell types produce potentially osteoclast-activating cytokines. It is not clear which of these cytokine pathways is most important. The fall in ovarian production of androgens and progesterone also contributes to some of these changes. Estrogen also has effects outside bone that may contribute to menopausal bone loss, as shown in the shaded area to the right. 28

Bone Loss Due to Sex Steroid Deficiency in Men
-6 -4 -2 2 10 20 30 Bioavailable E2, pg/mL Change in Mid-Radius BMD, %/yr r = 0.05 P = 0.702 r = 0.36 P = 0.003 • Bioavailable T and E2 decline with normal aging • Bone loss in men is best correlated with bioavailable E2 • Bioavailable E2 is a determinant of bone mass in men, as in women Khosla, S., et al. J Clin Endocrinol Metab : , with permission, Copyright 2001, The Endocrine Society.

-- Calcium / Vitamin D Deficiency -- Trauma Low bone mass/ impaired bone quality Inadequate peak bone mass Early menopausal bone loss Decrease in bone mass/bone quality Calcium/ vitamin D deficiency Other factors Fractures The pathophysiology of osteoporosis in the elderly is complex. Age-related bone loss is accelerated by deficiency of calcium or vitamin D. 30

Calcium Nutrition is Poor in the Elderly

Vitamin D is required to prevent bone loss and fractures
Modified from Dawson-Hughes BoneKEy 2(12):39-41.

Pathogenesis of Bone Loss Due to Calcium/Vitamin D Deficiency in the Aged
Secondary hyperparathyroidism BONE LOSS Decreased calcium absorption Low dietary Calcium intake Decreased sunlight exposure Decreased vitamin D synthesis Impaired renal function Estrogen deficiency High bone turnover and bone loss with aging is partly explained by secondary hyperparathyroidism. The genesis of secondary hyperparathyroidism is complex. On the one hand, nutritional calcium intakes are often inadequate. On the other, the proportion of intestinal calcium absorption that is absorbed is reduced in the aged, because of a combination of estrogen deficiency, inadequate vitamin D nutrition and declining renal function, with reduced synthesis of the active vitamin D metabolite 1,25(OH)2D. 33

-- Other Factors -- Trauma Low bone mass/ impaired bone quality Inadequate peak bone mass Early menopausal bone loss Decrease in bone mass/bone quality Calcium/ vitamin D deficiency Other factors Fractures The pathophysiology of osteoporosis in the elderly is complex. In addition to ageing, menopause and calcium/vitamin D deficiency, other factors can also contribute, as shown on the next slide. 34

Some additional Risk Factors for Bone Loss in Women and Men
Chronic respiratory disorders Homocystinuria Immobilization Neoplastic diseases Osteogenesis Imperfecta Renal insufficiency Rheumatoid arthritis Systemic mastocytosis Thyrotoxicosis Vitamin D deficiency Anemias hemoglobinopathies Hypogonadism Glucocorticoid excess Alcohol, tobacco abuse GI/hepatic disorders Hyperparathyroidism Hypercalciuria Anticonvulsants

-- Trauma -- Trauma Low bone mass/ impaired bone quality Inadequate peak bone mass Early menopausal bone loss Decrease in bone mass/bone quality Calcium/ vitamin D deficiency Other factors Fractures The pathophysiology of osteoporosis in the elderly is complex. Most osteoporotic fractures occur with trauma to a bone whose strength has been reduced. 36

Most Osteoporotic Fractures Occur in a Fall
Risk Factors for Falls Risks for Fracture in a Fall • Failure to break a fall • Falling to the side • Age • Low bone mass • Unfavorable bone geometry • High bone turnover • Muscle weakness • Poor balance • Poor eyesight • Benzodiazepine use • Poor overall health

Genetics of Osteoporosis
Stuart H. Ralston 38

Family history predicts fractures in early postmenopausal women
2 4 6 8 10 3.7 fold increase Post-menopausal or Hysterectomy Family History Hip Fracture Previous Fracture Spine BMD Heel Ultrasound Adjusted Odds Ratio • Random population sample of 1857 women aged years • Family history had greater predictive value than 1SD fall in bone density The importance of genetic factors in osteoporosis is reflected by the fact that patients with osteoporotic fractures often have a positive family history of the condition. In the example shown, women who had a positive family history of hip fracture had a 3.7 fold increased risk of fracture when compared with women without a family history. This risk is greater than a 1 standard deviation reduction in spine BMD or heel ultrasound, personal history of previous fracture, and being postmenopausal or having a hysterectomy Adapted from J Bone Miner Res 1996;11: with permission of the American Society for Bone and Mineral Research for slides as presented by IBMS BoneKEy. 39

Quantitating the Genetic Contribution to Complex Traits Using Twins
Dizygotic 100% 50% Genes Shared Heritability of bone Phenotypes BMD % Biochemical % Markers Hip Geometry % Fracture % Resemblance MZ Twin 1 Twin 2 r = 0.7 DZ r = 0.3 Monozygotic Having a positive family history of a condition does not prove it is genetic, since family members also tend to share the same environment. Twin study provide a way to dissect out the relative importance of genes and environment. These studies take advantage of the fact that monozygotic (MZ) twins share 100% of their genes in common, whereas dizygotic twins share only 50%. If a specific trait such as BMD (or disease) has a genetic component, the resemblance between MZ twins with respect to that trait or disease should be closer than in DZ twins, reflecting the importance of shared genes as opposed to shared environment in disease causation. The most commonly used measure of this resemblance is heritability which can range from 0% (no genetic component) to 100% (completely genetic). Twin studies have shown that several phenotypes relevant to the pathogenesis of osteoporosis have a genetic component including BMD, biochemical markers of bone turnover, and femoral neck geometry. Fracture itself has a lower heritability reflecting the greater importance of environmental factors such as falls to the pathogenesis of this complication of osteoporosis. 40

Techniques for Gene Mapping
X • Linkage analysis in families or sibpairs • Linkage analysis in animals • Candidate gene association studies Osteoporosis is a complex disease that does not exhibit classic Mendelian inheritance and multiple genes with environmental interactions are likely to be involved. The methods available for genetic mapping of complex traits include: linkage analysis in families and in sib pairs, linkage studies in inbred strains of mice and candidate gene association studies in unrelated individuals. Each of these designs has advantages and disadvantages. Linkage studies are statistically robust and unlikely to give false positive results, but have limited power to detect genes of modest effect, such as those that have been implicated in the pathogenesis of osteoporosis. Linkage studies in mice represent a powerful way of detecting loci for complex diseases; environment can be carefully controlled thus minimising the influence of confounding factors; large numbers of progeny can be generated, giving excellent statistical power; and fine mapping can be achieved by repeated back crosses onto the parental strain. A drawback is that the genes which regulate BMD in mice may not necessarily be the same as the ones that regulate BMD in humans. Candidate gene association studies are relatively easy to perform and can detect genetic variants which have modest effects on the phenotype of interest. The main disadvantage is the possibility of false positive (or false negative) results due to confounding factors and population stratification. 41

Osteoporosis Pseudoglioma Syndrome
A Locus for High BMD and low BMD on the Same Region of Chromosome 11q12-13 Osteoporosis Pseudoglioma Syndrome HBM Family LOD Chr 11 D11S905 D11S987 D11S937 1.0 3.0 5.0 7.0 HBM linkage OPPS linkage Linkage studies have been spectacularly successful in identifying the genes responsible for monogenic bone diseases. In this example, linkage analysis was used to localize the genes responsible for two monogenic diseases with opposite phenotypes; the high bone mass syndrome (HBM) characterized by dominant inheritance of increased BMD and the osteoporosis pseudoglioma syndrome (OPPS), characterised by severe, early onset osteoporosis with vitreous opacities in the eye. The genes responsible for many other monogenic diseases characterised by abnormalities of bone mass have also been identified by linkage analysis over the past 5 years including Sclerosteosis, van Buchem disease and various forms of osteopetrosis. Gong, Y., et al. Am J Hum Genet : Johnson, M. L., et al. Am J Hum Genet : ; Gong Y et al. Cell. 2001;107(4):513-23, with permission, copyright © 2001 by Cell Press. 42

Identification of BMP2 as a candidate gene for osteoporosis
-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 50 100 Severe OP Spine OP Chromosome 20p12 Lodscore Distance (cM) 4.0 5.0 4.5 3.5 5.5 Hip OP BMP2 Ser37Ala Controls 0.8% Cases 4.8% p<0.0007 C20orf42 LOC1605 C20orf155 C20orf154 CHGB Linkage studies in isolated populations have also been successful in identifying genes that predispose to osteoporosis. A study of patients and their relatives in Iceland resulted in the identification of a region of significant linkage to osteoporosis–related phenotypes on chromosome 20p12, and positional cloning studies showed that this was partly explained by a missense polymorphism in the BMP2 gene, which was present in about 5% of osteoporotic subjects when compared with less than 1% of controls. Linkage studies have also been performed in outbred populations to identify the genes that regulate BMD using various study designs, including the analysis of twins, sib pairs and extended families. There has been little replication of linkage regions between these studies, emphasising the polygeneic nature of the condition. Another finding to emerge has been the realisation that different genes may be responsible for regulation of BMD in men and women and at different skeletal sites, which emphasises the complexity and challenges that will need to be addressed to identify the genes that influence the risk of osteoporosis in different clinical situations. Styrkarsdottir U et al. PLoS Biol :E69. 43

Some Candidate Genes Which Have Been Studied in Osteoporosis
Hormones & receptors • Vitamin D Receptor • Estrogen Receptors • Androgen Receptor • PTHr1 • PTH • Calcitonin Receptor • TNFRSF11B • Calcium Sensing Receptor • LRP5 • PPARγ • Aromatase Cytokines & Growth Factors • IL-1 • IL-1ra • IL-6 • TGFb • SOST Bone Matrix • COLIA1 • Collagenase • alpha-2-HS-glycoprotein • Osteocalcin • Apolipoprotein E A large number of candidate gene studies have been performed in osteoporosis, although in many cases the studies have been small, poorly designed and underpowered. These genes have been chosen on the basis of their functional effects on the regulation of calcium metabolism, on bone remodelling and on bone matrix. Current evidence suggests that most candidate gene polymorphisms have modest effects on BMD and other phenotypes relevant to the pathogenesis of osteoporosis – in the order of standard deviation units. The sample size required to detect genetic effects of this magnitude are in the order of individuals, depending on the allele frequency of the polymorphism being studied. 44

Type I Collagen, Osteogenesis Imperfecta and the Genetics of Osteoporosis
“blue” eyes in OI fractures in OI Collagen is the major protein of bone • Proteins encoded by COLIA1 and COLIA2 genes • Collagen genes produce alpha 1 and alpha 2 chains • Chains assemble to form collagen fibres Mutations in collagen coding regions cause extreme bone fragility and severe Osteoporosis •“brittle bone disease” • osteogenesis imperfecta (OI) One of the most widely studied candidate genes is COLIA1 which is known to be mutated in osteogenesis imperfecta, a disease characterised by low BMD and extreme bone fragility. In this disease, mutations occur which affect the protein coding regions of the COLIA1 or COLIA2 gene, resulting in under production of collagen or in the production of abnormal collagen which is rapidly degraded. 45

Polymorphism of a Sp1 Binding Site in the Collagen Type 1 Alpha 1 Gene
G/G - “SS” ~ 70% G/T - “Ss” ~ 25% T/T - “ss” ~ 5% GGGAATG GGGCGGGAT GAGGGCT---- +1240 +1260 T G Sp1 Exon 1 Exon 2 Sp1 sites COLIA1 17q21 Polymorphism While screening of the collagen genes in osteoporotic patients has excluded the presence of protein coding mutations, a common polymorphism has been described which affects a binding site for the transcription factor Sp1 within the first intron of the COLIA1 gene – a region known to be important in COLIA1 regulation. Grant, S.F., et al. Nat Genet :203-5 46

Mechanisms of Bone Fragility in Patients with COLIA1 Sp1 Polymorphism
+ Polymorphism Sp1 binding COLIA1 transcription Defective mineralisation 0.0 0.5 1.0 1.5 2.0 2.5 SS Ss ss Any fracture Fracture Risk (Odds ratio) Genotype Vertebral fracture a 1 (I) homotrimer a1(I) chain overproduced Functional studies have shown that the COLIA1 Sp1 polymorphism increases the affinity for transcription factor binding, and increases collagen transcription, resulting in the formation of COLIA1 homotrimers (abnormal collagen molecules consisting of three alpha 1 chains). This leads to subtle defects in mineralisation and increases bone fragility predisposing to fractures. A meta-analysis of published studies indicates that the risk of fracture increases by about 50% per copy of the “s” (thymidine) allele and predisposes to fracture by mechanisms that are independent of differences in BMD. Mann, et al. A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. 47

XbaI Polymorphisms of ESR1 Predict Fractures Independent of BMD
1.2Kb ~20 Kb Xba-I Exon 1 TA repeat Pvu-II Exon 2 Oestrogen Receptor alpha ESR1 (6q25.1) Genomos Study XX vs. Xx vs. xx .2 .4 .6 .8 1 Odds ratio for any fracture (95% CI) .1 2 4 6 Women RE Women FE Total RE Total FE Rotterdam D Rotterdam F Oxagen M Oxagen F Florence F DOPS F Cambridge M Cambridge F Barcelona F Aberdeen F Aarhus F The estrogen receptor alpha (ESR1) is another important candidate gene for osteoporosis. Several common polymorphisms (left panel) have been described in the first intron of ESR1, recognised by the restriction enzymes PvuII and XbaI; and a TA repeat polymorphism has been identified in the promoter. A recent large scale study performed in almost 18,917 individuals from 5 European countries showed that the XbaI polymorphism of ESR1 predicted fractures independent of BMD (right panel), indicating that ESR1 might regulate fracture risk through an effect on bone quality as well as bone density. Ioannidis et al. JAMA 2004;292(17): , with permission, Copyright © 2004 American Medical Association 48

Clinical Applications of Research in Osteoporosis Genetics
• Better understanding of why osteoporosis occurs • Finding genetic markers to identify people at risk of fracture and to target therapy • Identifying genes that are targets for the design of new drugs Studies on the genetic basis of osteoporosis have many clinical applications. They offer the prospect of allowing us to better understand why the disease occurs; the development of genetic markers to target treatments more effectively and to identify people at risk of fracture; and finally they will provide new molecular targets that will form the focus for design of new drugs to prevent and treat osteoporosis. 49

Diagnosis of Osteoporosis
Nelson Watts Ian Reid

Osteoporosis Osteoporosis can be diagnosed based on the presence or history of a low-trauma fracture; however, a fracture is not required for diagnosis. The diagnosis of osteoporosis can also be based on bone mineral density (BMD). Osteoporosis can be diagnosed based on the presence or history of a low-trauma fracture; however, a fracture is not required for diagnosis. The diagnosis of osteoporosis can also be based on bone mineral density (BMD). 51

An Operational Definition
WHO Criteria for Postmenopausal Osteoporosis An Operational Definition Category T-score Normal -1.0 and above Low bone mass (osteopenia) -1.0 to -2.5 Osteoporosis -2.5 and below The T-score compares an individual’s BMD with the mean value for young normal individuals and expresses the difference as a standard deviation score. Adapted from J Bone Miner Res 1994;9: with permission of the American Society for Bone and Mineral Research for slides as presented by IBMS BoneKEy.

Why the WHO Choose -2.5 "Such a cutoff value identifies approximately 30% of post-menopausal women as having osteoporosis using measurements made at the spine, hip, or forearm. This is approximately equivalent to the lifetime risk of fracture at these sites." Kanis JA, et al. J Bone Miner Res 1994; 9:1137 Adapted from J Bone Miner Res 1992;7: and J Bone Miner Res 1995;10: with permission of the American Society for Bone and Mineral Research for slides as presented by IBMS BoneKEy.

DXA BMD: Basis for Comparison
Results Expressed as Standard Deviation Score T-score: • Compared with mean peak bone mass • Assess what is desirable • Used to assess fracture risk Z-score: • Compared with age- and gender matched controls • Assess what is expected • Used to determine if bone mass is unusually low

Demographics Image Results T- & Z-scores Graph Graph
A typical report of BMD by DXA is shown here. It includes patient demographics, an image of the region in which BMD was measured, the numerical results (BMD, T-score and Z-score) and a graph of the patients BMD compared to age-adjusted normal values. Graph Graph 55

Who Should Have a Bone Density Test?
Yes All men with a fragility fracture Men aged  70 years Anyone considering therapy for osteoporosis Anyone receiving treatment for osteoporosis Diseases/conditions/drugs causing osteoporosis All women with a fragility fracture All women  65 with risk factor Women with risk factor Women  65 years of age ISCD AACE NOF US PSTF Patient Category The value of BMD to determine fracture risk depends on the individual’s age, previous fracture history and other risk factors. The utility of BMD determinations for population screening is controversial, and recommendations for use of BMD tests vary widely within a given country, as illustrated by recommendations in the US, and around the world. USPTF. Ann Intern Med :526-8 Leib, E. S., et al. J Clin Densitom :1-6 Endocr Pract 7: 57

Biochemical Markers of Bone Turnover
Formation osteoblasts Resorption osteoclasts Resorption Markers • Pyridinoline (Pyr) • Deoxypyridinoline (dPyr) • Amino terminal telopeptide of type I collagen (NTX) • Carboxyl terminal telopeptide of type I collagen (CTX) Formation Markers • Osteocalcin (OC) • Bone-specific alkaline phosphatase (BAP) • Amino terminal propeptide of type I collagen (PINP) • Carboxyl terminal propeptide of type I collagen (PICP) Numerous biochemical markers of bone turnover can be measured in serum and urine. Most are byproducts of the synthesis or degradation of type I collagen, which is the principal structural protein of bone matrix. The amino terminal propeptide (PINP) and carboxyterminal propeptide (PICP) of type I collagen are cleaved off during assembly of collagen chains. The origin of collagen telopeptides and crosslinks during bone resorption is illustrated on the next slide. Bone formation rates can also be assessed by measuring the bone-specific component of serum alkaline phosphatase or the serum level of another constitutent of bone matrix, osteocalcin. 58

Origin of Collagen Cross Links
CTx NTx N-TELOPEPTIDE REGION HELICAL REGION C-TELOPEPTIDE Pyr Dpd Bone resorption involves breakdown of type I collagen. The rate of bone resorption can be estimated by measuring collagen degradation products. Collagen chains are crosslinked by pyridinoline (Pyr) and deoxypyridinoline (Dpd) rings formed by condensation of lysine residues. Collagen degradation releases crosslinked fragments of the amino-terminal region (N-telopeptides) and the carboxyl-terminal region (C-telopeptides). The crosslinks themselves (Pyr and Dpd) can also measured in urine. Watts, N. B. Clin Chem : , with permission. 59

Effect of Age and Menopause on Bone Turnover % Increase Over Premenopausal Levels
** 50 100 Urinary CTx Urinary NTx * Bone Formation Bone Resorption Serum OC Serum BAP * < 0.01 ** < 0.001 75 25 Perimenopausal Early Perimenopausal and Postmenopausal (< 10 yrs) Late Perimenopausal and Postmenopausal (> 10 yrs) On average there is a marked increase in markers of both bone formation and bone resorption at the time of menopause, which persists for more than 10 years after menopause. High bone turnover in postmenopausal women may predispose to fractures by effects on microarchitecture or the material properties of bone. Fracture prevention by antiresorptive agents (e.g. bisphosphonates and SERMs) is correlated more strongly with reduction in bone turnover than with changes in BMD. Adapted from J Bone Miner Res 1996;11: with permission of the American Society for Bone and Mineral Research for slides presented by IBMS BoneKEy. 60

Not Everyone with Osteoporosis Has High Bone Turnover
84 Elderly Women with Osteoporosis Garnero, P., et al. J Clin Endocrinol Metab : , with permission, Copyright 1994, The Endocrine Society.

Bone Markers in Osteoporosis
Potential Role Value Assess causation Seldom needed Assess fracture risk CV and assay standardization issues Treatment selection Value unproven Assess response to treatment Limited by precision and uncertain cost-benefit Improve compliance Uncertain cost-benefit Monitor therapy discontinuation May be necessary without an evidence base Many potential roles for bone turnover markers in the management of osteoporosis have been proposed, but none is universally accepted. There is little evidence that determining whether a subject had high- or low-turnover osteoporosis is relevant to treatment selection. Bone turnover markers are of value in fracture risk assessment. However, there is no agreement as to which marker is most useful in this role, and no evidence that the addition of markers to clinical and densitometric assessment is cost-effective. Also, the day-to-day variability of markers, variations in standardization of different assays for the same marker, and uncertainties regarding the definition of the premenopausal range, all limit the practical utility of this approach. Reproducibility of marker measurements is also a limitation in their use for assessing response to treatment, though some of the newer markers appear to be more stable and therefore more able to reliably distinguish subjects who have not shown the expected response to anti-resorptive therapy. However, compelling evidence is lacking that this information improves compliance, above what is achieved with simple patient counselling. 62

Treatment of Osteoporosis
Harold Rosen Ian Reid Gordon J Strewler

Fracture Risk Reduction in Osteoporosis
Risk Factors Therapies • Bone loss/low BMD Calcium/D deficiency Estrogen deficiency • Tendency to fall Muscle weakness Poor balance • Preserve/increase BMD Calcium/D supplementation Drug therapy • Fall prevention Strengthening exercises, vit D Balance exercise Therapy is targeted to pathophysiological risk factors for fractures, such calcium/vitamin D deficiency and factors such as estrogen deficiency that cause loss of bone mineral. Patients with osteoporosis are also at risk for fracture because of a tendency to fall; most fractures are the result of a fall onto a fragile bone. Observational studies show that low levels of physical activity and poor muscle strength are risk factors for fracture, and randomized trials show that exercise will improve muscle strength and reduce the risk of falling. However, there are no randomized, placebo-controlled trials demonstrating fewer fractures among exercisers. 64

Calcium and Vitamin D for the Treatment of Osteoporosis
Many studies suggest that calcium and vitamin D supplementation will decrease the risk of fractures. The left panel shows the incidence of nonvertebral fractures in 3270 ambulatory elderly women who were randomized to receive either 1,200 mg of calcium and 800 units of vitamin D or placebo. The incidence of hip fractures and of all non-vertebral fractures was significantly lower in the supplemented group. The right panel illustrates the results of a different study of 389 adults age >65 who were randomized to receive either 500 mg of calcium and 700 units of vitamin D daily or placebo. Treatment was associated with an improvement in BMD and a decrease in incidence of all non-vertebral fractures. While not all randomized trials agree that treatment with calcium and vitamin D will reduce the risk of fractures, there are enough data to suggest safety and efficacy to recommend 800 units of vitamin D and 1200 mg of calcium daily. Chapuy, M. C., et al. N Engl J Med : , with permission, Copyright © 1992 Massachusetts Medical Society. All rights reserved. Dawson-Hughes, B., et al. N Engl J Med :670-6, with permission, Copyright © 1997 Massachusetts Medical Society. All rights reserved. 65

Changes in BMD with Calcium + Vitamin D
-1.0* -6.4 Trochanter +2.7* -4.6 Total Hip +2.9* +1.8 Fem Neck Ca/D Placebo Site +0.06* -1.09 Total body +2.12* +1.22 Spine (L2-4) +0.50* -0.70 *p < 0.05 Chapuy et al. Dawson-Hughes et al. Chapuy et al, N Engl J Med 1992;327:1637, with permission, Copyright © 1992 Massachusetts Medical Society. All rights reserved. Dawson-Hughes et al, N Engl J Med 1997;337:670, with permission, Copyright © 1997 Massachusetts Medical Society. All rights reserved. The changes in BMD that occur with treatment with calcium and vitamin D are small. This slide summarizes the changes in BMD in the 2 studies shown in the previous slide. In the panel on the right, changes in BMD with vitamin D + calcium are modest at best, but still resulted in a substantial and significant reduction in fracture risk. There is therefore speculation that treatment with calcium and vitamin D reduce the incidence of fractures by other means as well, as illustrated in the next slide. 66

Vitamin D Prevents Falls: Meta-analysis
(95% Cl) 0.47 ( ) 0.68 ( ) 0.53 ( ) 0.69 ( ) 0.91 ( ) 0.69 ( ) Odds Ratio Source Pfeifer et al, 2000 Bischoff et al, 2003 Gallagher et at, 2001 Dukas et al, 2004 Graafmans et al, 1996 Pooled (Uncorrected) Favors Control Vitamin D 0.1 0.5 1.0 5.0 10.0 In addition to modest increases in BMD, treatment with calcium and vitamin D reduces the likelihood of falls, according to this metaanalysis of five randomized clinical trials. This effect of vitamin D therapy may have to do with improved muscle function and strength. Redrawn from Bischoff-Ferrari H et al JAMA Apr 28;291(16): , with permission, Copyright © 2004 American Medical Association. All rights reserved. 67

Indications for Treatment of Postmenopausal Osteoporosis
in Three US Guidelines NOF AACE NAMS Prior fragility fracture Vertebral or hip Any fracture With low BMD Vertebral only T-score Without risk factor < -2.0 < -2.5 With risk < -1.5 Risk factors 5 Major, 8 Additional Several, including risk of falling Thin, family history, prior fracture

Drug Treatments for Osteoporosis
Antiresorptive • Bisphosphonates alendronate, risedronate, ibandronate, etidronate • SERMs (Selective estrogen receptor modulators) raloxifene • Estrogen • Calcitonin Anabolic • PTH

Bisphosphonates Inhibit Bone Resorption by Preventing Formation of the Ruffled Border

Mean % Change from Placebo
Effect of Different Drugs for Osteoporosis on BMD and Vertebral Fracture Risk Lumbar Spine BMD Relative Risk of Incident Vertebral Fractures Raloxifene 60 mg Prevalent VFx { Raloxifene 60 mg No Prevalent VFx Alendronate 5/10 mg Prevalent VFx Alendronate 5/10 mg No Prevalent VFx Risedronate 5mg North American Risedronate 5mg Multinational Nasal Calcitonin 200IU Teriparatide 20 g Ibandronate 2.5mg Strontium Ranelate* Zoledronic Acid 0.2 0.4 0.6 0.8 1.0 1 2 3 4 5 6 7 8 Mean % Change from Placebo Relative Risk  95% CI Modified from Marcus R, et al. Endocr Rev :16-37, with permission, Copyright 2002, The Endocrine Society. Drug approved for treatment of osteoporosis have been proven in randomized clinical trials to improve BMD and decrease the rate of vertebral fractures compared to calcium and vitamin D alone. Data from different trials are not directly comparable, because the clinical trials differed in number and types of patients enrolled. The data shown here are taken from a review article (Marcus R et al. Endocrine Reviews 2002;23:16) and updated with pivotal trials of more recently approved agents, teriparatide, ibandronate, strontium ranelate and zoledronic acid. Some individual agents have subsequently been compared with one another in head-to-head trials: PTH and alendronate; alendronate and calcitonin, alendronate and raloxifene, alendronate and risedronate, and estrogen and alendronate. 71

Effect of Different Drugs for Osteoporosis on Non-Vertebral Fracture Risk
Relative Risk Incident Non-Vertebral Fractures Raloxifene 60 & 120 mg Prevalent & No Prevalent VFx Alendronate 5/10mg Prevalent VFx Alendronate 5/10mg No Prevalent VFx Alendronate 10mg Low BMD Risedronate 5mg Prevalent VFx Risedronate 5mg Prevalent VFx Risedronate 2.5 & 5mg Osteoporosis Drug approved for treatment of osteoporosis have been proven in randomized clinical trials to improve BMD and decrease the rate of nonvertebral fractures compared to calcium and vitamin D alone. Data from different trials are not directly comparable, because the clinical trials differed in number and types of patients enrolled. The data shown here are taken from a review article (Marcus R et al. Endocrine Reviews 2002;23:16) and updated with pivotal trials of more recently approved agents, teriparatide, ibandronate, strontium ranelate and zoledronic acid. In pivotal trials, raloxifene, calcitonin and ibandronate did not significantly reduce the incidence of nonvertebral fractures, although all three agents reduced the incidence of vertebral fractures. Nasal Calcitonin 200IU Prevalent VFx Teriparatide 20g Prevalent VFx Ibandronate Strontium Ranelate* Zoledronic Acid 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Modified from Marcus R, et al. Endocr Rev :16-37, with permission, Copyright 2002, The Endocrine Society. Relative Risk  95% CI 72

Quality of evidence for antifracture efficacy of therapies in postmenopausal osteoporosis
SPINE NON-VERTEBRAL HIP Alendronate A A A Calcitonin C C D Calcitriol C C - Calcium + vitamin D - C C Cyclic etidronate B D D Ibandronate A - - Estrogen A A A Evidence-based analysis of the efficacy of therapy for postmenopausal osteoporosis, based on the WHO Osteoporosis Taskforce Report (WHO Scientific Group, Prevention and Management of Osteoporosis. World Health Organization, Geneva, 2003), updated. A: Positive evidence from one or more, adequately powered, randomized controlled trials; B: Positive evidence from smaller non-definitive randomized controlled trials; C: Inconsistent results from randomized controlled trials; D: Positive results from observational studies; - efficacy not established or tested. Raloxifene A - - Risedronate A A A Strontium ranelate A A - Teriparatide A A - Zoledronic acid A A A A, Large RCT; B, Small RCT; C, RCT are inconsistent; D, Observational studies Updated from WHO Osteoporosis Taskforce Report (WHO 2003), with permission, copyright © 2003 World Health Organization. 73

Follow-up of Patients on Treatment for Osteoporosis
Minimal follow-up • Verify that patient is taking the medication • Verify appropriate dosing procedure for bisphosphonates • Verify that patient is taking sufficient calcium and vitamin D Optional • Bone density – not usually before 2 years • Bone turnover markers – role is uncertain - some physicians use them to confirm compliance, but biological and measurement variation are a problem

Pro’s and Con’s of Available Osteoporosis Therapies
Agent Pro’s Con’s Calcium/Vit D Cheap, accessible Partial efficacy HRT Effective breast ca, DVT, MI, CVA Raloxifene  vert Fx,  breast ca Less effect on BMD Bisphosphonates  vert and nonvert Fx GI intolerance Strontium Bulky, daily dosing ? Mechanism Teriparatide Effective Expensive, daily injections

An Introduction to Clinical Osteoporosis

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