Advances in Osteoporosis Management

Joan Parambi January 14th 2009

-New findings regarding the pathophysiology of osteoporosis.

-Identifying who needs to be treated. -Current treatment guidelines. -Monitoring therapy. -Areas of future development.

In 2002 NOF(National Osteoporosis Foundation)published the projected prevalence of those aged

50 and older based on yr 2000 census3:

2002 2010 2020Women with osteoporosis: 7.8 9.1 10.5Women with low bone mass: 21.8 26 30.4Men with osteoporosis: 2.3 2.8 3.3Men with low bone mass: 11.8 14.4 17.1 (number in millions)

Incidence and Economic Burden of Osteoporosis-Related Fractures in the United States, 2005–2025.Russel Burge,, Bess Dawson Hughes, Daniel H Solomon, John B Wong, Alison King,Anna Tosteson.

Projected annual direct costs of osteoporosis $25.3billion by 202541

Osteoporotic fractures accounted for: ~17 billion in direct medical costs. 41

>400,000 hospital admissions.42

~2.5million physician visits. 42

>180,000 nursing home admissions42

Bone is comprised of 2 components:

40% organic collagenous 60% inorganic (mineral)

matrix providing tensile mostly in the form ofstrength. Calcium

hydroxyapetite providing compressive strength.

Metabolic bone disease categorized by histology :

Osteoporosis OsteomalaciaDecrease in matrix Bone matrix

intactand mineral. reduced mineral.Osteoporosis defintion by NIH Consensus Conference, 2000: Skeletal disorder characterized by

compromised bone strength predisposing to an increased risk of fracture.

Bone strength= Bone density + Bone quality1

Canalis E et al. N Engl J Med 2007;357:905-916

Signals that determine the

differentiation, function, and death of these cells and their

progenitors determine how many units are activated over time, how active and well-balanced the basic multicellular unit is, and whether, at the end of the cycle, bone mass will be gained, lost, or stable4


Bone morphogenetic proteins : members of TGF beta superfamily of polypeptides, which includes activins and inhibins.5 These proteins bind to and activate specific receptors to initiate signal transduction and influence intracellular events leading to osteoblastogenesis 6, 7

Wnt :uses a Wnt– beta-catenin signaling pathway.8 Wnt binds to specific receptors, and to low-density lipoprotein receptor–related proteins 5 and 6 (LRP5 and LRP6). This stabilizes the beta-catenin which translocates into the nucleus and regulates gene expression.

IGF-I: made in the liver and other tissues, including the skeleton, mediates the effects of growth hormone

on longitudinal bone growth.9 IGF-I exerts direct actions in bone and is necessary for skeletal development and the maintenance of bone mass.9 It acts both as a circulating growth hormone–dependent hormone and as a local skeletal growth factor influenced by PTH.10,11,12 IGF-I primarily influences the differentiated

function of the osteoblast and prevents osteoblast apoptosis

PTH-related protein: produced by bone and cartilage cells has developmental and local regulatory function.13,14 Its secretion by lactating mammary glands may play a role in the increased rate of bone resorption and rapid bone loss that occurs in lactating women.15

Fibroblast growth factor: produced by bone and connective tissue. Regulated by PTH, prostaglandin E2, TGF-beta. It decreases collagen synthesis in vitro but can stimulate bone formation in vivo. 16,17

Cytokine Bone resorption Bone formation Prostaglandins

Interleukin-1 + - +

TNF-alpha + - +

Interleukin-4 - - -

Interleukin-6 + + +

Interleukin-7 + ? ?

Interleukin-11 + + ?

Interleukin-13 - ? -

Interleukin-18 - ? ?

Leukemia Inhibitory factor

- + +

Interferon-gamma - - -

Uptodate: Pathogenesis of osteoporosis 18

Whyte M. N Engl J Med 2006;354:860-863

RANKL: a member of the TNF superfamily of

ligands and receptors, is essential for the differentiation, activation, and survival of bone-resorbing osteoclasts.19 It is expressed on the surface of marrow stromal cells, activated T cells, and precursors of bone-forming osteoblasts . 19 RANKL accelerates osteoclastogenesis when it binds to its receptor, RANK, on osteoclast precursor cells to enhance nuclear factor- B and other signaling pathways.19 Osteoprotegerin that is produced by osteoblasts, the key modulator of RANKL, acts as a soluble decoy receptor for RANKL and blocks its effects

Parathyroid hormone - is the most important regulator of calcium

homeostasis. It maintains serum calcium concentrations by: Stimulating bone resorption Increasing renal tubular calcium reabsorption Increasing renal calcitriol production.

PTH stimulates bone formation when given intermittently, but inhibits collagen synthesis at high concentrations 26,27. It stimulates osteoclast mediated bone resorption when given (or secreted) continuously. It also stimulates gene expression and increases the production of several local factors, including IL-6, IGF-1 and an IGF-binding protein, IGF-BP-5, and prostaglandins. 28,37.


Calcitriol : increases intestinal calcium and phosphorus absorption, thereby promoting bone mineralization. At high concentrations, under conditions of calcium and phosphate deficiency, it also stimulates bone resorption, thereby helping to maintain the supply of these ions to other tissues.

Calcitonin : inhibits osteoclasts and therefore bone resorption in pharmacologic doses. However, its physiologic role is minimal in the adult skeleton. Its effects are transient, probably because of receptor downregulation.

Growth hormone and IGFs : The GH/IGF-1 system and IGF-2 are important for skeletal growth, especially growth at the cartilaginous end plates and endochondral bone formation.

Glucocorticoids : Have both stimulatory and inhibitory effects on bone cells. Essential for differentiation of osteoblasts and sensitize bone cells to regulators

of bone remodeling. Inhibition of bone formation is the major cause of glucocorticoid-induced

osteoporosis and may be due to accelerated apoptosis of osteoblasts and osteocytes 38

Thyroid hormones: stimulate both bone resorption and formation. Thus, bone turnover is increased in hyperthyroidism, and bone loss can occur. 39

Estrogen and Androgen: reduces rate of bone loss by many local effects like:

Reducing the number and depth of resorption cavities.44 Promoting osteoclast apoptosis.40

Increasing TGF-beta release from osteoblasts Inhibiting release of TNF-alpha

Is based on Clinical risk factors BMD measurement.

Using the above data a FRAX score can be calculated.

Ebeling P. N Engl J Med 2008;358:1474-1482

Raisz L. N Engl J Med 2005;353:164-171

Raisz L. N Engl J Med 2005;353:164-171

1. Dual-Energy X-Ray Absorptiometry:

Results expressed as• T-SCORE is the number of SD the

measurement is above or below the YOUNG-NORMAL MEAN BMD.

• Z-SCORE is the number of SD the measurement is above or below the AGE-MATCHED MEAN BMD.

Sites used for measurement per WHO criteria:

• Total proximal femur• Femoral neck• Lumbar spine• 33percent(1/3rd)radius if e/o OA or

surgery at other 3 sites.

Peripheral skeletal sites predict global # risk, however not used in WHO/FRAX criteria therefore limited value. Changes to therapy at these sites are slow.

2. Quantitative ultrasonography (QUS) — does not measure BMD, but instead measures the transmission of ultrasound through accessible limb bones or the reflectance of the ultrasound waves from the bone surface.

3. Quantitative computed tomography (QCT): measures volumetric BMD (vBMD) in mg/cm3, most often at the spine. Unlike DXA, QCT can isolate trabecular bone from its envelope of cortical bone. The studies are split regarding its superiority to DXA.

4. Emerging technologies :High resolution microCT and microMRI allow noninvasive three-dimensional

evaluation of bone microarchitecture. These techniques are used primarily in research settings.

In 2008, a WHO task force introduced a Fracture Risk Assessment Tool (FRAX), which estimates the 10-year probability of hip fracture or major osteoporotic fractures combined (hip, spine, shoulder, or wrist) for an untreated patient using femoral neck T-score or Z-score and easily obtainable clinical risk factors for fracture 50.

FRAX is based upon data collected from large prospective observational studies of men and women of different ethnicities and from different world regions in which clinical risk factors, BMD, and fractures were evaluated 51,52 . FRAX has been validated in 11 independent cohorts, mainly comprised of women 53. The statistical power of this large dataset allows estimation of fracture probability from an individual's set of risk factors.

The country-specific FRAX prediction algorithm is available online at (http://www.shef.ac.uk/FRAX/). 54

In the United States, cost-effectiveness modeling suggests that the 10-year hip fracture probability at which treatment becomes cost-effective (intervention threshold) ranges from 2.5 to 4.7 percent for women and from 2.4 to 4.9 percent in men, depending upon age and assuming annual treatment costs of $600 and a willingness-to-pay threshold of $60,000 . 55

http://www.shef.ac.uk/FRAX/

Uses: They can give some indication about the future risk for bone loss and

fractures. Useful in monitoring the efficacy of antiresorptive therapy in patients

with osteoporosis

Markers indicating rate of bone formation:• Serum bone-specific ALP reflects the cellular activity of osteoblasts

56,57,58

• Serum osteocalcin reflects its rate of synthesis by osteoblasts. • Serum concentration of the carboxy-terminal and amino terminal

propeptides of type I collagen (PICP and PINP, respectively) reflects changes in synthesis of new collagen. 59

Markers indicating rate of bone resorption:• Serum skeletal acid phosphatase .• Urinary excretion of collagen crosslinks {deoxypyridinoline (DPD) and

the peptide-bound alpha-1 to alpha-2 N-telopeptide crosslinks (NTX), and the c-telopeptide crosslink (CTX)} reflects bone resorption and not dietary intake. 60

Initial laboratory tests :• Complete chemistry profile (including alkaline phosphatase) • CBC• Calcium, phosphorus • 25 hydroxyvitamin D • Urinary calcium excretion

Additional laboratory tests if indicated(clinical features/ low Z-score)• 24 hour urine for free cortisol • Estradiol, FSH, LH, Prolactin , TSH• Magnesium • 1,25 dihydroxyvitamin D ,Intact PTH • Celiac screen • SPEP/UPEP• ESR, Rheumatoid Factor• Serum tryptase and histamine levels • Homocysteine • Skin biopsy for connective tissue disorders • COL1A genetic testing for osteogenesis imperfecta • Serum and urine markers of bone turnover

History of hip or vertebral fracture.

Other prior fractures and T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine, as measured by dual-energy X-ray absorptiometry (DXA).

T-score -2.5 (DXA) at the femoral neck, total hip, or spine, after appropriate evaluation to exclude secondary causes.

T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine and secondary causes associated with high risk of fracture, such as glucocorticoid use or total immobilization.

T-score between -1 and -2.5 at the femoral neck, total hip, or spine, and a 10-year probability of hip fracture 3 percent or a 10-year probability of any major osteoporosis-related fracture 20 percent based upon the US-adapted WHO algorithm.

Rosen C. N Engl J Med 2005;353:595-603

Antiresorptive agents:• Zoledronic acid 5 mg administered intravenously once yearly.

• Calcitriol: effective in preventing glucocorticoid-induced and posttransplant-related bone loss.

• Strontium ranelate :is an orally active drug consisting of two atoms of stable strontium and an organic moiety (ranelic acid). In animal studies, strontium appears to inhibit bone resorption and increase bone formation . Its mechanism of action in humans is less certain. Approved for use in Europe only.

Anabolic agents• Denosumab — investigational humanized monoclonal antibody against RANKL .

Encouraging Phase 2 trial results.

• Tibolone — a synthetic steroid whose metabolites have estrogenic, androgenic, and progestagenic properties used in some countries.

ISCD : recommends follow-up BMD testing (DXA spine and hip) when the expected change in BMD equals or exceeds the least significant change (LSC), which is typically one year after initiation or change of therapy, with longer intervals once therapeutic effect is established. In conditions associated with rapid bone loss, such as glucocorticoid therapy, testing more frequently is appropriate 43

AACE : recommends annual DXA of the LS and proximal femur until stability is achieved, and every two years thereafter. 44

NAMS : recommends DXA of the total hip every two years. 45

Others: Conservative approach - takes the position that monitoring for

efficacy of antiresorptive therapy is unnecessary, as only a minority of patients continue to lose bone on therapy. 46,47,48

Bone turnover markers- if DXA cannot be performed at one year then measure fasting urinary NTX or serum CTX before and three to six months after starting antiresorptive therapy. 48,49 If the marker has fallen significantly (by 50 percent), the patient can be reassured that the next BMD measurement will likely be stable or improved . Repeat DXA can be done in 2 yrs.

12/15-lipoxygenase inhibitors: coded by the Alox15 gene which is up regulated in IL4 mediated bone resorption.20

Oral calcium sensing receptor antagonists : Administration leads to a transient rise in endogenous parathyroid hormone, similar to intermittently administered exogenous parathyroid hormone 21

Sclerostin inhibitors :Sclerostin is produced by osteocytes and inhibits bone formation 22. Antagonism of sclerostin might be associated with anabolic effects on bone. Monoclonal antibodies against sclerostin, for example, prevent its binding to Wnt coreceptors, enhancing Wnt signaling and increasing bone mass in rodents and nonhuman primates.23

Integrin antagonists : Integrins mediate the adhesion of osteoclasts to the bone surface, an important initial step for bone resorption 24

Cathepsin-K inhibitors — Cathepsin K is a protease that may play a role in osteoclast-mediated bone resorption .25

Antagonists of Dkk-1 : Mutations of LRP5 and LRP6 (wnt coreceptor) that lead to impaired binding of Dkk-1 are associated with increased bone mass.29 . Dkk-1 antibodies increased BMD, trabecular bone volume, and bone formation in rodents, suggesting that Dkk-1 inhibitors targeted specifically to bone might have potential

as an anabolic approach in the treatment of osteoporosis.30

Soluble Activin Receptors : Activin enhances osteoclastogenesis, and its effects on bone formation are controversial.31,32 A soluble activin receptor II, which binds activin and possibly bone morphogenetic protein 3, decreases bone resorption and enhances bone formation in rodents.33,34

The Osteoblast Proteasome and Its Inhibitors : Inhibitors of proteolytic processing systems might unmask or enhance anabolic pathways.35,36 The use of proteasome inhibitors will depend on their skeletal specificity and their safety profile, since such inhibitors can induce cellular toxic effects and the intracellular accumulation of misfolded proteins.35

1. NIH Consensus Conference, 2000.

2. Osteoporosis causes, diagnosis, and screening (uptodateonline)

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5. Canalis E, Economides AN, Gazzerro E. Bone morphogenetic proteins, their antagonists, and the skeleton. Endocr Rev 2003;24:218-235

6. Kawabata M, Imamura T, Miyazono K. Signal transduction by bone morphogenetic proteins. Cytokine Growth Factor Rev 1998;9:49-61.

7. Nohe A, Keating E, Knaus P, Petersen NO. Signal transduction of bone morphogenetic protein receptors. Cell Signal 2004;16:291-299.

8. Krishnan V, Bryant HU, MacDougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest 2006;116:1202-1209.

9. Bennett CN, Longo KA, Wright WS, et al. Regulation of osteoblastogenesis and bone mass by Wnt10b. Proc Natl Acad Sci U S A 2005;102:3324-3329.

10. Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 1998;19:717-797.

11. Canalis E, Centrella M, Burch W, McCarthy TL. Insulin-like growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures. J Clin Invest 1989;83:60-65.

12. Miyakoshi N, Kasukawa Y, Linkhart TA, Baylink DJ, Mohan S. Evidence that anabolic effects of PTH on bone require IGF-I in growing mice. Endocrinology 2001;142:4349-4356.

13. Strewler, GJ. The physiology of parathyroid hormone-related protein. N Engl J Med 2000; 342:177.

14. Miao, D, He, B, Jiang, Y, Kobayashi, T. Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34. J Clin Invest 2005; 115:2402.

15. VanHouten, JN, Dann, P, Stewart, AF, Watson, CJ. Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation. J Clin Invest 2003; 112:1429.

16. Hurley, M, Abreu, C, Harrison, JR, Lichtler, AC, Raisz, LG, Kream, BE. Basic fibroblast growth factor inhibits type I collagen gene expression in osteoblastic MC3T3-E1 cells. J Biol Chem 1993; 268:5588.

17. Mayahara, H, Ito, T, Nagai, H, et al. In vivo stimulation of endosteal bone formation by basic fibroblast growth factor in rats. Growth Factors 1993; 9:73.

18. Pathogenesis of osteoporosis . Lawrence G Raisz, MD, Clifford J Rosen, MD, Jean E Mulder, MD

19. Martin TJ. Paracrine regulation of osteoclast formation and activity: milestones in discovery. J Musculoskelet Neuronal Interact 2004;4:243-253

20. Klein RF, Allard J, Avnur Z, et al. Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science 2004;303:229-232.

21. Arey, BJ, Seethala, R, Ma, Z, et al. A novel calcium-sensing receptor antagonist transiently stimulates parathyroid hormone secretion in vivo. Endocrinology 2005; 146:2015.

22. Li, X, Ominsky, MS, Niu, QT, et al. Targeted Deletion of the Sclerostin Gene in Mice Results in Increased Bone Formation and Bone Strength*. J Bone Miner Res 2008;

23. Warmington K, Ominsky M, Bolon B, et al. Sclerostin monoclonal antibody treatment of osteoporotic rats completely reverses one year of ovariectomy-induced systemic bone loss. J Bone Miner Res 2005;20:Suppl 1:S22-S22.

24. Murphy, MG, Cerchio, K, Stoch, SA, et al. Effect of L-000845704, an alphaVbeta3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women. J Clin Endocrinol Metab 2005; 90:2022.

25. Tavares, FX, Boncek, V, Deaton, DN, et al. Design of potent, selective, and orally bioavailable inhibitors of cysteine protease cathepsin k. J Med Chem 2004; 47:588.

26. Greendale, GA, Wells, B, Marcus, R, Barrett-Connor, E. How many women lose bone mineral density while taking hormone replacement therapy? Results from the postmenopausal Estrogen/Progestin interventions trial. Arch Intern Med 2000; 160:3065.

27. Christgau, S, Rosenquist, C, Alexandersen, P, et al. Clinical evaluation of the serum CrossLaps One Step ELISA, a new assay measuring the serum concentration of bone-derived degradation products of type I collagen C-telopeptides. Clin Chem 1998; 44:2290.

21. Normal skeletal development and regulation of bone formation and resorption. Lawrence G Raisz, MD, Marc K Drezner MD, Jean E Mulder, MD(uptodate)

22. Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 2002;346:1513-1521

30. Grisanti M, Niu QT, Fan W, et al. Dkk-1 inhibition increases bone mineral density in rodents. J Bone Miner Res 2006;21:Suppl 1:S25-S25.

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32. Gaddy-Kurten D, Coker JK, Abe E, Jilka RL, Manolagas SC. Inhibin suppresses and activin stimulates osteoblastogenesis and osteoclastogenesis in murine bone marrow cultures. Endocrinology 2002;143:74-83.

33. Daluiski A, Engstrand T, Bahamonde ME, et al. Bone morphogenetic protein-3 is a negative regulator of bone density. Nat Genet 2001;27:84-88.

34. Pearsall RS, Cornwall-Brady M, Lachey J, Glatt V, Bouxsein ML. Treatment with a soluble activin type II receptor reverses bone loss in ovariectomized mice. J Bone Miner Res 2006;21:Suppl 1:S26-S26.

35. Kisselev AF, Goldberg AL. Proteasome inhibitors: from research tools to drug candidates. Chem Biol 2001;8:739-758. [

36. Garrett IR, Chen D, Gutierrez G, et al. Selective inhibitors of the osteoblast proteasome stimulate bone formation in vivo and in vitro. J Clin Invest 2003;111:1771-1782.

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41. Incidence and Economic Burden of Osteoporosis-Related Fractures in the United States, 2005–2025.Russel Burge,, Bess Dawson Hughes, Daniel H Solomon, John B Wong, Alison King,Anna Tosteson

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47. Christgau, S, Rosenquist, C, Alexandersen, P, et al. Clinical evaluation of the serum CrossLaps One Step ELISA, a new assay measuring the serum concentration of bone-derived degradation products of type I collagen C-telopeptides. Clin Chem 1998; 44:2290.

48. Ravn, P, Hosking, D, Thompson, D, et al. Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the early postmenopausal intervention cohort study. J Clin Endocrinol Metab 1999; 84:2363.

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54. http://www.shef.ac.uk/FRAX Accessed April 24, 2008.

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60. Hannon, R, Blumsohn, A, Naylor, K, Eastell, R. Response of biochemical markers of bone turnover to hormone replacement therapy: impact of biological variability. J Bone Miner Res 1998; 13:1124.

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