- Email: [email protected]
Pathophysiology and clinical manifestations of osteoporosis
Clinical Cornerstone
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Pathophysiology and Clinical Manifestations of Osteoporosis CAROLYN BECKER, IvlD Associate Director Toni Stabile Osteoporosis Center Columbia University New York, New York
Osteoporosis is a complex skeletal disorder in which compromised bone strength increases the risk of fragility fractures. Recent scientific advances in bone biology and immunology have greatly expanded our insights into the pathogenesis of osteoporosis. For those with osteoporotic fractures, however, the physical and psychological effects remain severe. Primary care physicians need to understand the basic mechanisms of bone physiology and pathophysiology in order to both prevent and treat this devastating disorder. (Clinical Cornerstone. 2006;811]:19-27) Copyright © 2006 Excerpta Medica, Inc.
In 1940, the prominent endocrinologist, Fuller Albright, described postmenopausal osteoporosis as a condition of impaired bone formation due to estrogen deficiency.1 Today, we know that the pathogenesis of osteoporosis is much more complex, involving genetics, systemic hormones, inflammatory cytokines, the immune system, growth factors, collagen abnormalities, neural pathways, and a variety of other influences yet to be discoveredfl In its simplest definition, osteoporosis is a disorder in which reduced bone strength results in an increased risk of fracture. 3 Bone strength in turn depends on bone mineral density (BMD) (the amount of bone tissue) and bone quality (the structure and material composition of bone). BMD can be easily measured by dual energy x-ray absorptiometry (DXA) and other techniques, but bone quality must be inferred. Low BMD, poor bone quality, or both can greatly increase the risk of a fracture.4 New insights into bone quality suggest that fragility fractures occur when the structure or material composition of bone can no longer adapt to the mechanical and physical demands of the skeleton. 5 These factors, along with an increased risk of falls, contribute to a high incidence of fragility fractures in patients with osteoporosis.
KEY
POINT
Osteoporosis is a disorder of low BMD, poor bone quality, or both.
damage; or (3) inadequate bone formation occurs in response to bone resorption. Certain fractures, such as hip, wrist, and humerus, are further influenced by the frequency and direction of falls. Peak bone mass is the maximum BMD achieved by age 40 years, as measured by DXA. 6 Peak bone mass is a major predictor of BMD later in life but varies greatly according to sex, ethnicity, body size, and even region of bone. In a recent cohort study of 359 Chinese American women, peak bone mass occurred at age 20 to 29 years at the femoral neck but not until age 40 to 49 years at the lumbar spine and total hip. 7 On average, men have larger bones and higher peak bone masses than women) Studies in twins show that up to 80% of the variance in peak bone mass is accounted for by genetic factors,9,1° while nutrition, hormonal status, habits, exercise, medications, and medical illnesses account for the rest. Low BMD at the time of menopause predicts a higher rate of fracture over the next 10 years. 11 Therefore, efforts to increase peak bone mass by improving calcium and vita-
BASIC CONCEPTS Osteoporosis develops when any of the following occur: (1) peak bone mass is less than optimal; (2) excessive bone resorption causes loss of bone mass and structural
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rain D intake, performing weight-bearing exercises, and making healthy lifestyle choices early in life should result in lower rates of osteoporosis and fractures later in life, though this has not been definitively proven. 6
KEY
POINT
resorption, or inadequate bone f o r m a t i o n can all lead to osteoporosis.
During childhood and adolescence, bone formation exceeds bone resorption, leading to a net gain of bone mass. For a number of years after peak bone mass is achieved, the rates of bone resorption and bone formation remain balanced. However, with the onset of menopause in women and normal aging in both sexes, this balance is disrupted and BMD, bone structure, and bone quality all begin to deteriorate. The rate at which this occurs and the pattern and type of bone loss are most likely genetically determined.6,12 BONE
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osteoblasts, and osteocytes. Osteoclasts and osteoblasts compose the bone multicellular unit (BMU), where bone remodeling and reconstruction occur. At the BMU, a small packet of old or damaged bone tissue is removed by the osteoclast in a process known as bone resorption. Osteoblasts are then recruited to the excavated site to fill it in with new, young, healthy bone tissue (bone formation). This occurs continuously throughout the skeleton and is critical for normal bone strength. Osteoclast and osteoblast functions are well coordinated or coupled. Osteocytes, the most numerous and longest-lived bone cells, act as the mechanosensors for the skeleton and are actually derived from senescent osteoblasts. They form an intricate communication network with each other and with the outer bone surface, and, in response to mechanical and structural demands, they direct where and when bone remodeling will occur. 5 Since the time needed for osteoclasts to resorb bone is short (weeks), while the time needed for osteoblasts to form bone is long (months), any process in adults that increases the rate of bone remodeling will result in a net loss of bone. Additionally, as the number of unfilled excavation pits increases, they form stress risers, which are vulnerable sites that can easily perforate and result in microfractures. Excessive bone resorption can also result in complete dropout of trabecular plates, leaving no template upon which bone formation can occur. The pattern of complete loss of trabecular structures is particularly common among postmenopausal women, while aging
L o w peak bone mass, excessive bone
NORMAL
•
PHYSIOLOGY
To understand the pathophysiology of osteoporosis, it is necessary to review normal bone physiology (Figure 15). Bone is living tissue and its strength depends upon the normal functioning of 3 key bone cells: osteoclasts,
Blood vessel
New lining cells Lining cells
\
~: ~
--Osteoid
Osteob,asts Osteoclasts
h
I \
"-'~
,"
New bone m
osteocytes
1
--Cement line I --Old
,
/ i
Figure I. The bone remodeling cycle on a trabecula. Reprinted with permission, s 20
bone
Clinical C o r n e r s t o n e
men tend to have thinning of trabeculae rather than total dropout. 13 During childhood and puberty, high rates of bone resorption are accompanied by even higher rates of bone formation. But with aging, for unknown reasons, the osteoblastic response to bone resorption is inadequate and resorption outstrips formation. This osteoblastic failure is a major factor in the pathogenesis of osteoporosis. 2 In recent years, researchers have uncovered the fundamental molecular mechanisms by which osteoclasts and osteoblasts coordinate their activities at the BMU (Figure 214). A key cytokine, called RANKL (receptor activator of nuclear factor-~zB ligand), is produced by osteoblasts and activated T cells within the bone marrow and plays a major role in the intercellular communication network. 15 RANKL binds to the receptor activator of nuclear factor ~:B (RANK) receptor, which is expressed on the surface of osteoclasts and osteoclast precursors. When RANKL binds to RANK, it promotes the differentiation of osteoclast precursors from an early stage of maturation into fully mature, multinucleated, and functional osteoclasts. RANKL can also activate mature osteoclasts, stimulating these cells to begin resorbing bone. In addition, RANKL binds to osteoprotegerin (OPG), a soluble decoy receptor produced by numerous hematopoietic cells. OPG, by sequestering RANKL and preventing its binding to RANK, functions as a potent antiresorptive cytokine. 15 The RANKL/RANK/OPG system appears to be the final common pathway through which all processes that stimulate bone resorption must go. Denosumab, a promising new
1,25-dihydrox~itaminD3 Osteoprotegerin PTH ~f RANKL ~ NF-KBand •
/
| Strornalcell Interleukin.ll
Osteoclast precursor
pathways
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antiresorptive drug for postmenopausal osteoporosis, is a monoclonal antibody directed against RANKL; the drug is in Phase III clinical trials at this time. 16
KEY
POINT
The R A N K L / R A N K / O P G system is the final common pathway for bone resorption.
ESTROGEN
DEFICIENCY
Though Fuller Albright recognized the important link between estrogen deficiency and bone loss in postmenopausal women, the effects of estrogen deficiency on bone physiology are much more complex than he envisioned. 1 In postmenopausal women, the rate of bone turnover increases dramatically and remains elevated for up to 40 years, leading to continuous, progressive bone loss. 17 Contrary to Albrighrs original hypothesis, a marked increase in bone resorption, and not impaired bone formation, appears to be the primary stimulus for bone loss in the setting of acute estrogen deficiency, since rates of both resorption and formation are increased immediately after menopause. 18,19 Men do not experience an abrupt cessation of gonadal function comparable to menopause, but they do experience a gradual age-related loss of bone associated with declines in unbound (ie, bioavailable) sex steroids. These declines are the result of progressive increases in circulating sex hormone-binding globulin (SHBG), the major circulating sex steroid-binding protein. 2° Epidemiologic studies suggest that SHBG may have an effect on bone loss and fracture risk independent of its role as a binding protein. 21 Decreases in local formation of estradiol from testosterone (via decreases in aromatase enzyme activity) may play an additional role in the pathophysiology of male osteoporosis. 22 Thus, estrogen deficiency is critical to the pathophysiology of both male and postmenopausal osteoporosis. How does estrogen deficiency lead to bone loss? It has been clearly shown that osteoblasts, osteocytes, and osteoclasts express functional estrogen receptors. 23 These receptors are also expressed in bone marrow stromal cells, the precursors of osteoblasts, which provide physical support for future osteoclasts, T-cells, [3-cells, and most other cells in the human bone marrow. Through a complex
Osteoclast
~
•
"
Bone
Prostaglandin E2
Figure 2. The RANKL/RANK/OPG system and osteoclast formation. RANKL = receptor activator of nuclear factor (NF)-~cB ligand; RANK = receptor activator of nuclear factor ~cB; OPG = osteoprotegerin; PTH = parathyroid hormone; JNK = Jun N-terminal kinase. Reprinted with permission. 14
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Parathyroid hormone (lYlH) levels begin to increase when the circulating form of vitamin D (25-hydroxyvitamin D) falls below 30 ng/mL, suggesting that the target for vitamin D supplementation should be at this level or higher.37 During the winter months, the seasonal decrease in vitamin D levels and increase in PTH levels are associated with an increase in fractures, independent of the increase in the rate of falling.38
POINT
Estrogen deficiency is a m a j o r cause of both male and postmenopausal osteoporosis.
interaction between the immune system and bone cells, estrogen deficiency causes T cells to release a variety of inflammatory cytoldnes. Some (eg, interleuldn [IL]-I, IL-6, and tumor necrosis factor-a) promote osteoclast recruitment, differentiation, and prolonged survival, whereas others (eg, IL-7) inhibit osteoblast differentiation and activity and cause premature death of osteoblasts (a process known as apoptosis). 24-27 This has led some to refer to postmenopausal osteoporosis as an inflammatory autoimmune disease triggered by estrogen deficiency.23 Though treatment with estrogen can reverse the inflammatory processes in bone, researchers are looking for new agents that can mimic the salutary effects of estrogen on bone without inducing the negative effects on organs such as the breast and heart.
O T H ER F A C T O R S A number of other factors implicated in the pathogenesis of osteoporosis that are beyond the scope of this article include the following: polymorphisms in the vitamin D receptor and other relevant genes; alterations in local and systemic growth factors, such as insulin-like growth factor-1 and bone morphogenic protein; effects of cytokines, prostaglandins, nitrous oxide, and leukotrienes; collagen abnormalities and elevations in homocysteine; and the influence of leptin and neural inputs from the sympathetic nervous system on bonefl CLINICAL
MANIFESTATIONS
Osteoporosis is generally a silent disease until a fragility fracture occurs. 39 The annual incidence of osteoporotic fractures exceeds 1.5 million in the United States.4° Among white women aged _>50years, -40% will experience a hip, spine, or wrist fracture during the remainder of their lives.41 Hip fractures, the most devastating type of osteoporotic fracture, are projected to increase from an estimated 1.7 million in 1990 to 6.3 million by the year 2050.42 Notably, 20% of patients die during the first year after a hip fracture, 43 nearly one third require nursing home placement after hospital discharge, and fewer than one third regain their prefracture level of physical functioning. 3,~ Vertebral fractures are associated with increased morbidity (back pain, height loss, deformity, and disability) and mortality.45 49 Among postmenopausal women who sustain a new vertebral fracture, 1 in 5 will experience another vertebral fracture in the next year. 5° Multiple thoracic fractures can result in restrictive lung disease, 51 progressive back pain, and disabling kyphosis. Other sequelae include constipation, abdominal pain and distention, reduced appetite, premature satiety, and weight loss. 52 The pain, physical limitations, and changes in lifestyle and appearance caused by osteoporotic fractures can have damaging psychological effects, including depression, loss of self-esteem, anxiety, fear, anger, and
C A L C I U M , V I T A M I N D, A N D PARATHYROI D H O R M O N E Particularly among the elderly, insufficient calcium intake, impaired intestinal absorption of calcium due to aging or disease, and deficiency of vitamin D can result in secondary hyperparathyroidism and bone loss. 28 Vitamin D deficiency and secondary hyperparathyroidism are extremely common among elderly patients admitted to hospitals with fragility fractures 29 and undoubtedly contribute to accelerated bone loss and increasing skeletal fragility, as well as to neuromuscular weakness that can increase the risk of falls.3°-32 Clinical trials involving older individuals at high risk for calcium and vitamin D deficiency indicate that supplementation of both can reverse secondary hyperparathyroidism, decrease bone resorption, increase bone mass, reduce fracture rates, and even decrease the frequency of fallsfl8'33'34 However, in some recent large studies, calcium and vitamin D supplementation did not reduce fracture incidence significantly, perhaps because the populations studied were less deficient in calcium and/or vitamin D than other populations studied. 35,36
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10. Howard GM, Nguyen TV, Harris M, et al. Genetic and environmental contributions to the association between quantitative ultrasound and bone mineral density measurements: A twin study. J Bone Miner Res. 1998;13: 1318-1327. 11. Stewart A, Kumar V, Reid DM. Long-term fracture prediction by DXA and Q U S - - a 10-year prospective study. J Bone Miner Res. 2006;21:413-418. 12. Pantsulaia I, Trofimov S, Kobyliansky E, Livshits G. Contribution of the familial and genetic factors on monocyte chemoattractant protein- 1 variation in healthy human pedigrees. Cytokine. 2005;32:117-123. 13. Khosla S, Riggs BL, Atkinson EJ, et al. Effects of sex and age on bone microstructure at the ultradistal radius: A population-based noninvasive in vivo assessment. J Bone Miner Res. 2006;21:124-131. 14. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664. 15. Khosla, S. Minireview: The OPG/RANKL/RANK system. Endocrinology. 2001; 142:5050-5055. 16. McClung MR, Leweicki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821-831. 17. Garnero R Sornay-Rendu E, Chapuy MC, Delmas PD. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res. 1996;11:337-349. 18. Parfitt AM, Villanueva AR, Foldes J, Rao DS. Relations between histologic indices of bone formation: Implications for the pathogenesis of spinal osteoporosis. J Bone Miner Res. 1995;10:466-473. 19. Ebeling PR, Atley LM, Guthrie JR, et al. Bone turnover markers and bone density across the menopausal transition. J Clin Endocrinol Metab. 1996;81:3366-3371. 20. Riggs BL, Khosla S, Melton LJ III. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002;23:279-302. 21. Goderie-Plomp HW, van der Klift M, de Ronde W, et al. Endogenous sex hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: The Rotterdam Study. J Clin Endocrinol Metab. 2004;89:3261-3269. 22. Van Pottelbergh I, Goemaere S, Kaufman JM. Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. J Clin Endocrinol Metab. 2003;88: 3075-3081. 23. Weitzmann MN, Pacific R. Estrogen deficiency and bone loss: An inflammatory tale. J Clin Invest. 2006;116:11861194. 24. Weitzmann MN, Pacifici R. The role of T lymphocytes in bone metabolism. Immunol Rev. 2005;208:154-168. 25. Weitzmann MN, Roggia C, Toraldo G, et al. Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. J Clin Invest. 2002;110:1643-1650. 26. Gilbert L, He X, Farmer R et al. Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology. 2000;141:3956-3964.
strained relationships with family and friends.53 55 These adverse physical and psychological outcomes following an osteoporotic fracture can precipitate social isolation, physical deterioration, and worsening frailty,
KEY
•
POINT
Osteoporotic fractures cause serious physical and psychological sequelae.
SUMMARY We have come a long way in our understanding of osteoporosis in the 66 years since Fuller Albright first described the disease in postmenopausal women. The pathogenesis of osteoporosis is complicated and multifaceted, involving genetics, cellular immunity, inflam-
mation, and complex systems of hormonal signaling and regulation. Over time, insights into these basic mechanisms should greatly improve our care of patients with osteoporotic fractures and help prevent fractures in those at greatest risk,
REFERENCES 1. Albright F, Bloomberg E, Smith PH. Postmenopausal osteoporosis. Trans Assoc Am Physicians. 1940;55: 298305. 2. Raisz L. Pathogenesis of osteoporosis: Concepts, conflicts, and prospects. J Clin Invest. 2005;115:3318-3325. 3. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. ,lAMA. 2001;285:785-795. 4. Felsenberg D, Boonen S. The bone quality framework: Determinants of bone strength and their interrelationships, and implications for osteoporosis management. Clin Ther 2005;27:1-11. 5. Seeman E, Delmas PD. Bone quality--the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354:2250-2261. 6. Mora S, Gilsanz V. Establishment of peak bone mass. Endocrinol Metab Clin North Am. 2003;32:39-63. 7. Walker MD, Babbar R, Opotowsky AR, et al. A referent bone mineral density database for Chinese American women. Osteoporos Int. 2006;17:878-887. 8. Seeman E. Sexual dimorphism in skeletal size, density, and strength. J Clin Endocrinol Metab. 2001;86:45764584. 9. Sambrook PN, Kelly PJ, Morrison NA, et al. Scientific review. Genetics of osteoporosis. Br J Rheumatol. 1994; 33:1007-1011. 23
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27. Cenci S, Weitzmann MN, Roggia C, et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-c~. J Clin Invest. 2000;106:1229-1237. 28. Lips R Vitamin D deficiency and secondary hyperparathyroidism in the elderly: Consequences for bone loss and fractures and therapeutic implications. Endocr Rev. 2001; 22:477-501. 29. Becker C, Crow S, Toman J, et al. Characteristics of elderly patients admitted to an urban tertiary care hospital with osteoporotic fractures: Correlations with risk factors, fracture type, gender and ethnicity. Osteoporos Int. 2006; 17:410-416. 30. Boonen S, Bischoff-Ferrari HA, Cooper C, et al. Addressing the musculoskeletal components of fracture risk with calcium and vitamin D: A review of the evidence. Calcif Tissue Int. 2006;78:257-270. 31. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of vitamin D on falls: A meta-analysis. JAMA. 2004;291:1999-2006. 32. Sambrook PN, Chen JS, March LM, et al. Serum parathyroid hormone predicts time to fall independent of vitamin D status in a frail elderly population. J Clin Endocrinol Metab. 2004;89:1572-1576. 33. Bischoff-Ferrari HA, Orav EJ, Dawson-Hughes B. Effect of cholecalciferol plus calcium on falling in ambulatory older men and women: A 3-year randomized controlled trial. Arch Intern Med. 2006;166:424-430. 34. Bischoff HA, Stahelin HB, Dick W, et al. Effects of vitamin D and calcium supplementation on falls: A randomized controlled trial. J Bone Miner Res. 2003; 18:343-351. 35. Grant AM, Avenell A, Campbell MK, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): A randomised placebocontrolled trial. Lancet. 2005;365:1621-1628. 36. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683. 37. Lips R Which circulating level of 25-hydroxyvitamin D is appropriate? J Steroid Biochem Mol Biol. 2004;89-90: 611-614. 38. Pasco JA, Henry MJ, Kotowica MA, et al. Seasonal periodicity of serum vitamin D and parathyroid hormone, bone resorption, and fractures: The Geelong Osteoporosis Study. J Bone Miner Res. 2004; 19:752-758. 39. National Osteoporosis Foundation. Physician's guide to prevention and treatment of osteoporosis. Available at: http ://www'n° f'°rg/-vti-birdshtml'dll/physguide/index'htm" Accessed October 1, 2006. 40. National Osteoporosis Foundation. America's Bone Health: The State o f Osteoporosis and Low Bone Mass in Our Nation. Washington, DC: National Osteoporosis Foundation; 2002.
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41. US Dept of Health and Human Services. Bone Health and Osteoporosis: A Report o f the Surgeon General. Rockville, MD: US Dept of Health and Human Services, Public Health Service, Office of the Surgeon General; 2004. 42. Cummings SR, Melton LJ III. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359:1761-1767. 43. National Institutes of Health. Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement. 2000;17: 1-45. 44. Empana JR Dargent-Molina R Breart G, and the EPIDOS Group. Effect of hip fracture on mortality in elderly women: The EPIDOS prospective study. J Am Geriatr Soc. 2004;52:685-690. 45. Ensrud E, Thompson DE, Cauley JA, et al, and the Fracture Intervention Trial Research Group. Prevalent vertebral deformities predict mortality and hospitalization in older women with low bone mass. J A m Geriatr Soc. 2000; 48:241-249. 46. Kado DM, Browner WS, Palermo L, et al, and the Study of Osteoporotic Fractures Research Group. Vertebral fractures and mortality in older women: A prospective study. Arch Intern Med. 1999;159:1215-1220. 47. Nevitt MC, Ettinger B, Black DM, et al. The association of radiographically detected vertebral fractures with back pain and function: A prospective study. Ann Intern Med. 1998;128:793-800. 48. Johnell O, Kanis JA, Oden A, et al. Mortality after osteoporotic fractures. Osteoporos Int. 2004; 15:38-42. 49. Miyakoshi M, Itoi E, Kobayashi M, Kodama H. Impact of postural deformities and spinal mobility on quality of life in postmenopausal osteoporosis. Osteoporos Int. 2003; 14: 1007-1012. 50. Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA. 2001;285:320-323. 51. Lombardi I, Oliveira LM, Mayer AF, et al. Evaluation of pulmonary function and quality of life in women with osteoporosis. Osteoporos Int. 2005;16:1247-1253. 52. Lane NE. Epidemiology, etiology and diagnosis of osteoporosis. Am J Obstet Gynecol. 2006;194(Suppl 1):$3Sll. 53. Gold DT. The nonskeletal consequences of osteoporotic fractures. Psychologic and social outcomes. Rheum Dis' Clin North Am. 2001;27:255-262. 54. Adachi JD, Ioannidis G, Olszynski WR et al. The impact of incident vertebral and non-vertebral fractures on health related quality of life in postmenopausal women. BMC Musculoskelet Disord. 2002;3:11. 55. Johnell O, Kanis J. Epidemiology of osteoporotic fractures. Osteoporos Int. 2005;16(Suppl 2):$3-$7.
Address correspondence to: Carolyn Becker, MD, Toni Stabile Osteoporosis Center, Columbia University, 180 Fort Washington Avenue, Harkness Pavillion, Room 904, New York, NY 10032. E-mail: [email protected] 24
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Dialogue Box EDITORIAL
BOARD
Do osteocytes retain the ability to differentiate into osteoclasts and osteoblasts?
EDITORIAL
BOARD
How do estradiol levels compare in men versus women?
BECKER
BECKER
No, osteoclasts and osteoblasts do not come from osteo-
Surprisingly, it turns out that postmenopausal women
cytes. Instead, they are derived from hematopoietic pre-
have lower estradiol levels than men. The average serum
cursors and mesenchymal stem cells, respectively. Osteo-
estradiol level in men can range from 25 to 50 pg/mL,
cytes are senescent osteoblasts imbedded in the bone
whereas in women it often falls well below 20 pg/mL.
matrix. EDITORIAL B O A R D EDITORIAL B O A R D
Is estrogen more important than testosterone in
Although senescent, don't osteocytes play an impor-
maintaining bone integrity in men?
tant role in maintaining bone strength? BECKER
BECKER
Yes, and estrogen plays a critical role throughout the
Yes. We used to think the osteocytes were dormant and
life cycle of men. During puberty, estradiol is needed
not doing much. It turns out they are absolutely critical
for maturation of the male skeleton and closure of
for the health of the bone. Osteocytes are responsible
the epiphyses. After maturity, estrogen appears more
for sensing the mechanical stresses and structural
important than testosterone in maintaining bone min-
demands on the skeleton and detecting areas of micro-
eral density (BMD). This has been demonstrated in
damage. Once a microcrack in the bone is detected, using an intricate cell-to-cell communications network, osteocytes are able to recruit osteoclasts and osteoblasts to the areas where bone remodeling needs to occur. Avascular necrosis results from the death of osteocytes. Osteocyte apoptosis is also found in osteonecrosis of the jaw due to bisphosphonate therapy. EDITORIAL B O A R D What is the mechanism for osteoporosis occurring in patients with hyperthyroidism?
elegant studies of men given gonadotropin-releasing hormone agonists that shut off pituitary gonadotrophs and cause a fall in testosterone production. If you selectively give these subjects either testosterone coupled with an aromatase inhibitor (which prevents testosterone conversion to estrogen) or estrogen alone, it turns out the estrogen is more effective in preventing bone loss than testosterone. Large epidemiologic studies have also found that although bone loss, osteoporosis, and fractures in men do not correlate well with testosterone levels, a strong correlation
BECKER
exists with estradiol levels. An event that really revo-
Basically any process that accelerates bone turnover
lutionized this field occurred about 10 years ago with
in adults, whether hyperthyroidism, postmenopausal
the report of a young man with open epiphyses, linear
estrogen deficiency, or hyperparathyroidism, results in
growth well into his late 20s, and significant osteo-
increased bone resorption. In adults, this leads to bone
porosis. This young man had a mutation in the aro-
loss because the time needed for osteoclasts to resorb
matase gene that caused him to have plenty of testos-
bone is much shorter than the time needed by
terone in his body but no estrogen. Treatment of this
osteoblasts to fill in the bone. So, there is a net loss of
young man with estrogen produced an increase in
bone in all cases of high bone turnover.
bone density and fusion of his epiphyses.
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Dialogue Box EDITORIAL
is more important. However, in patients with chron-
BOARD
Does this mean that with regard to osteoporosis, the
ic obstructive pulmonary disease, there have been
efficacy of testosterone replacement is dependent on
some nice studies comparing supplementation with
its conversion to estrogen?
25-hydroxyvitamin D versus 1,25-dihydroxyvitamin D.
BECKER
more efficacious in improving BMD and preventing
In these patients, the 1,25-dihydroxyvitamin D was Yes, in part. Perhaps 60% to 70% is an estrogen effect
fractures than 25-hydroxyvitamin D. For most elderly
and the remainder is an independent testosterone effect.
patients, however, we really focus on keeping the
So both estrogen and testosterone are important for the
25-hydroxyvitamin D level above 30 ng/mL.
male skeleton. EDITORIAL EDITORIAL
BOARD
What agents are available for stimulating osteoblast
BOARD
Can you explain the mechanism by which vitamin D
activity?
supplementation reduces the risk of falls? BECKER
Although continuous exposure to parathyroid hormone
BECKER
Vitamin D is my favorite hormone since it has multiple
(PTH), as in primary or secondary hyperparathyroidism,
beneficial properties. Vitamin D has a direct effect on
turns on the receptor activator of nuclear factor-~zB
myocytes and muscle fibers, in addition to its effects on
ligand system and causes increased bone resorption,
bone. A number of studies have looked at fall risk inde-
PTH administered in an intermittent manner (as with
pendent of bone density and found that if you take a
teriparatide), activates a totally different biochemical
group of people from a nursing home and you put half
pathway that stimulates osteoblasts. Other osteoblast-
of them on calcium alone and the other half on calcium
activating agents include growth hormone, insulin growth
and vitamin D, you will find significantly fewer falls in
factor-l, and strontium ranelate, which is available in
the latter group within 3 months. Physiologic testing
Europe. Interestingly, if you could develop a statin that
has demonstrated improved muscle strength, gait, and
went predominantly to the bone instead of to the liver,
reduced body sway simply by repleting vitamin D in
it would be anabolic.
patients deficient in this vitamin. In addition to direct effects on muscle and bone, vitamin D may favorably
EDITORIAL
impact the immune system and offer antitumor effects
Since the age at which peak BMD is achieved
as well.
appears genetically programmed, if for some reason
BOARD
there is a delay in achieving peak BMD, is there a EDITORIAL
period of "catch-up"?
BOARD
Is the deficiency with 1,25-dihydroxyvitamin D or with 25-hydroxyvitamin D?
BECKER
To a certain extent it depends on how early the delay BECKER
occurs--for example, if a young woman has a year of
That's a good question. It turns out that you can have total-
anorexia nervosa in her early teens but then has full
ly normal 1,25-dihydroxyvitamin D levels in the setting of
nutritional and hormonal recovery, there may be nearly
deficient 25-hydroxyvitamin D and still have osteomala-
total catch-up growth in BMD. But if she misses that
cia, increased fall risk, and muscle weakness. So you need
critical window of time--for most Caucasian women in
both. For muscle and bone, we think 25-hydroxyvitamin D
their 20s--once the window closes, it closes. After that,
26
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Dialogue Box even if the eating disorder, amenorrhea, or other sec-
amounts of calcium and vitamin D, to exercise, and to
ondary disorder is cured, the BMD will never get any
refrain from smoking. In addition, it is prudent for
higher than it was at the time of her genetically pro-
women to avoid using it for a prolonged period of time
grammed attainment of peak bone mass. That's why I
since it may prevent achievement of optimal peak
emphasize that osteoporosis is really a pediatric disease
BMD.
that presents in adulthood. The peak bone mass you accrue during childhood, adolescence, and young adult-
EDITORIAL BOARD
hood is the maximum you can achieve.
Is there any value to getting a dual energy x-ray a b s o r p t i o m e t r y (DXA) scan on a w o m a n on Depo-
EDITORIAL BOARD
Provera?
W h a t happens in the lactating female? BECKER BECKER
In a patient you deem at risk for osteoporosis based on
During lactation, women can lose a tremendous amount
other risk factors (such as family history, body build,
of bone. However, breastfeeding is not a risk factor for
cigarette use, or ethnicity), it's probably reasonable to
future fractures since rapid reversal of bone loss occurs
get a DXA scan. If the BMD is very low, you may want
after lactation ends.
to advise the young woman to find an alternative form of birth control.
EDITORIAL BOARD What's the current thinking with the risk associated
EDITORIAL BOARD
with depot m e d r o x y p r o g e s t e r o n e
What value on a DXA scan would be cause for
acetate (Depo-
Provera ® [Pharmacia & Upjohn, N.V/S.A., Puurs,
concern?
Belgium])? BECKER
BECKER
A Z-score of <2 SDs and certainly a Z-score <2.5 SDs
Depo-Provera clearly leads to lower BMD and bone loss
below age-matched women would be cause for concern.
due to reduced levels of estrogen. The bone loss is most
Even in a young woman with a Z-score of <2.5 SDs,
acute during the first 1 to 2 years of use and then it tends
however, I would not use the term "osteoporosis." Instead,
to slow down as a new equilibrium is reached. Once
I would tell her she has a BMD that is significantly below
Depo-Provera is discontinued, there is nearly complete
her peers and that by stopping Depo-Provera she could
recovery of BMD. The skeletal risk from Depo-Provera
improve her BMD. This recommendation has to be
depends on the duration of use and the age when it is
weighed against the risks and benefits of other forms of
started. It has not been definitively shown, however, to
birth control since preventing an unwanted pregnancy
be a risk factor for fractures. Young women who use
may take priority over the adverse skeletal effects from
Depo-Provera should be counseled to take in adequate
Depo-Provera.
27
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MANAGEMENT OF OSTEOPOROSIS
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Vol. 8, No. 1
Pathophysiology and Clinical Manifestations of Osteoporosis CAROLYN BECKER, IvlD Associate Director Toni Stabile Osteoporosis Center Columbia University New York, New York
Osteoporosis is a complex skeletal disorder in which compromised bone strength increases the risk of fragility fractures. Recent scientific advances in bone biology and immunology have greatly expanded our insights into the pathogenesis of osteoporosis. For those with osteoporotic fractures, however, the physical and psychological effects remain severe. Primary care physicians need to understand the basic mechanisms of bone physiology and pathophysiology in order to both prevent and treat this devastating disorder. (Clinical Cornerstone. 2006;811]:19-27) Copyright © 2006 Excerpta Medica, Inc.
In 1940, the prominent endocrinologist, Fuller Albright, described postmenopausal osteoporosis as a condition of impaired bone formation due to estrogen deficiency.1 Today, we know that the pathogenesis of osteoporosis is much more complex, involving genetics, systemic hormones, inflammatory cytokines, the immune system, growth factors, collagen abnormalities, neural pathways, and a variety of other influences yet to be discoveredfl In its simplest definition, osteoporosis is a disorder in which reduced bone strength results in an increased risk of fracture. 3 Bone strength in turn depends on bone mineral density (BMD) (the amount of bone tissue) and bone quality (the structure and material composition of bone). BMD can be easily measured by dual energy x-ray absorptiometry (DXA) and other techniques, but bone quality must be inferred. Low BMD, poor bone quality, or both can greatly increase the risk of a fracture.4 New insights into bone quality suggest that fragility fractures occur when the structure or material composition of bone can no longer adapt to the mechanical and physical demands of the skeleton. 5 These factors, along with an increased risk of falls, contribute to a high incidence of fragility fractures in patients with osteoporosis.
KEY
POINT
Osteoporosis is a disorder of low BMD, poor bone quality, or both.
damage; or (3) inadequate bone formation occurs in response to bone resorption. Certain fractures, such as hip, wrist, and humerus, are further influenced by the frequency and direction of falls. Peak bone mass is the maximum BMD achieved by age 40 years, as measured by DXA. 6 Peak bone mass is a major predictor of BMD later in life but varies greatly according to sex, ethnicity, body size, and even region of bone. In a recent cohort study of 359 Chinese American women, peak bone mass occurred at age 20 to 29 years at the femoral neck but not until age 40 to 49 years at the lumbar spine and total hip. 7 On average, men have larger bones and higher peak bone masses than women) Studies in twins show that up to 80% of the variance in peak bone mass is accounted for by genetic factors,9,1° while nutrition, hormonal status, habits, exercise, medications, and medical illnesses account for the rest. Low BMD at the time of menopause predicts a higher rate of fracture over the next 10 years. 11 Therefore, efforts to increase peak bone mass by improving calcium and vita-
BASIC CONCEPTS Osteoporosis develops when any of the following occur: (1) peak bone mass is less than optimal; (2) excessive bone resorption causes loss of bone mass and structural
19
Clinical Cornerstone
MANAGEMENT OF OSTEOPOROSIS
•
rain D intake, performing weight-bearing exercises, and making healthy lifestyle choices early in life should result in lower rates of osteoporosis and fractures later in life, though this has not been definitively proven. 6
KEY
POINT
resorption, or inadequate bone f o r m a t i o n can all lead to osteoporosis.
During childhood and adolescence, bone formation exceeds bone resorption, leading to a net gain of bone mass. For a number of years after peak bone mass is achieved, the rates of bone resorption and bone formation remain balanced. However, with the onset of menopause in women and normal aging in both sexes, this balance is disrupted and BMD, bone structure, and bone quality all begin to deteriorate. The rate at which this occurs and the pattern and type of bone loss are most likely genetically determined.6,12 BONE
Vol. 8, No. 1
osteoblasts, and osteocytes. Osteoclasts and osteoblasts compose the bone multicellular unit (BMU), where bone remodeling and reconstruction occur. At the BMU, a small packet of old or damaged bone tissue is removed by the osteoclast in a process known as bone resorption. Osteoblasts are then recruited to the excavated site to fill it in with new, young, healthy bone tissue (bone formation). This occurs continuously throughout the skeleton and is critical for normal bone strength. Osteoclast and osteoblast functions are well coordinated or coupled. Osteocytes, the most numerous and longest-lived bone cells, act as the mechanosensors for the skeleton and are actually derived from senescent osteoblasts. They form an intricate communication network with each other and with the outer bone surface, and, in response to mechanical and structural demands, they direct where and when bone remodeling will occur. 5 Since the time needed for osteoclasts to resorb bone is short (weeks), while the time needed for osteoblasts to form bone is long (months), any process in adults that increases the rate of bone remodeling will result in a net loss of bone. Additionally, as the number of unfilled excavation pits increases, they form stress risers, which are vulnerable sites that can easily perforate and result in microfractures. Excessive bone resorption can also result in complete dropout of trabecular plates, leaving no template upon which bone formation can occur. The pattern of complete loss of trabecular structures is particularly common among postmenopausal women, while aging
L o w peak bone mass, excessive bone
NORMAL
•
PHYSIOLOGY
To understand the pathophysiology of osteoporosis, it is necessary to review normal bone physiology (Figure 15). Bone is living tissue and its strength depends upon the normal functioning of 3 key bone cells: osteoclasts,
Blood vessel
New lining cells Lining cells
\
~: ~
--Osteoid
Osteob,asts Osteoclasts
h
I \
"-'~
,"
New bone m
osteocytes
1
--Cement line I --Old
,
/ i
Figure I. The bone remodeling cycle on a trabecula. Reprinted with permission, s 20
bone
Clinical C o r n e r s t o n e
men tend to have thinning of trabeculae rather than total dropout. 13 During childhood and puberty, high rates of bone resorption are accompanied by even higher rates of bone formation. But with aging, for unknown reasons, the osteoblastic response to bone resorption is inadequate and resorption outstrips formation. This osteoblastic failure is a major factor in the pathogenesis of osteoporosis. 2 In recent years, researchers have uncovered the fundamental molecular mechanisms by which osteoclasts and osteoblasts coordinate their activities at the BMU (Figure 214). A key cytokine, called RANKL (receptor activator of nuclear factor-~zB ligand), is produced by osteoblasts and activated T cells within the bone marrow and plays a major role in the intercellular communication network. 15 RANKL binds to the receptor activator of nuclear factor ~:B (RANK) receptor, which is expressed on the surface of osteoclasts and osteoclast precursors. When RANKL binds to RANK, it promotes the differentiation of osteoclast precursors from an early stage of maturation into fully mature, multinucleated, and functional osteoclasts. RANKL can also activate mature osteoclasts, stimulating these cells to begin resorbing bone. In addition, RANKL binds to osteoprotegerin (OPG), a soluble decoy receptor produced by numerous hematopoietic cells. OPG, by sequestering RANKL and preventing its binding to RANK, functions as a potent antiresorptive cytokine. 15 The RANKL/RANK/OPG system appears to be the final common pathway through which all processes that stimulate bone resorption must go. Denosumab, a promising new
1,25-dihydrox~itaminD3 Osteoprotegerin PTH ~f RANKL ~ NF-KBand •
/
| Strornalcell Interleukin.ll
Osteoclast precursor
pathways
MANAGEMENT OF OSTEOPOROSIS
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antiresorptive drug for postmenopausal osteoporosis, is a monoclonal antibody directed against RANKL; the drug is in Phase III clinical trials at this time. 16
KEY
POINT
The R A N K L / R A N K / O P G system is the final common pathway for bone resorption.
ESTROGEN
DEFICIENCY
Though Fuller Albright recognized the important link between estrogen deficiency and bone loss in postmenopausal women, the effects of estrogen deficiency on bone physiology are much more complex than he envisioned. 1 In postmenopausal women, the rate of bone turnover increases dramatically and remains elevated for up to 40 years, leading to continuous, progressive bone loss. 17 Contrary to Albrighrs original hypothesis, a marked increase in bone resorption, and not impaired bone formation, appears to be the primary stimulus for bone loss in the setting of acute estrogen deficiency, since rates of both resorption and formation are increased immediately after menopause. 18,19 Men do not experience an abrupt cessation of gonadal function comparable to menopause, but they do experience a gradual age-related loss of bone associated with declines in unbound (ie, bioavailable) sex steroids. These declines are the result of progressive increases in circulating sex hormone-binding globulin (SHBG), the major circulating sex steroid-binding protein. 2° Epidemiologic studies suggest that SHBG may have an effect on bone loss and fracture risk independent of its role as a binding protein. 21 Decreases in local formation of estradiol from testosterone (via decreases in aromatase enzyme activity) may play an additional role in the pathophysiology of male osteoporosis. 22 Thus, estrogen deficiency is critical to the pathophysiology of both male and postmenopausal osteoporosis. How does estrogen deficiency lead to bone loss? It has been clearly shown that osteoblasts, osteocytes, and osteoclasts express functional estrogen receptors. 23 These receptors are also expressed in bone marrow stromal cells, the precursors of osteoblasts, which provide physical support for future osteoclasts, T-cells, [3-cells, and most other cells in the human bone marrow. Through a complex
Osteoclast
~
•
"
Bone
Prostaglandin E2
Figure 2. The RANKL/RANK/OPG system and osteoclast formation. RANKL = receptor activator of nuclear factor (NF)-~cB ligand; RANK = receptor activator of nuclear factor ~cB; OPG = osteoprotegerin; PTH = parathyroid hormone; JNK = Jun N-terminal kinase. Reprinted with permission. 14
21
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KEY
MANAGEMENT OF OSTEOPOROSIS
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Vol. 8, No. 1
Parathyroid hormone (lYlH) levels begin to increase when the circulating form of vitamin D (25-hydroxyvitamin D) falls below 30 ng/mL, suggesting that the target for vitamin D supplementation should be at this level or higher.37 During the winter months, the seasonal decrease in vitamin D levels and increase in PTH levels are associated with an increase in fractures, independent of the increase in the rate of falling.38
POINT
Estrogen deficiency is a m a j o r cause of both male and postmenopausal osteoporosis.
interaction between the immune system and bone cells, estrogen deficiency causes T cells to release a variety of inflammatory cytoldnes. Some (eg, interleuldn [IL]-I, IL-6, and tumor necrosis factor-a) promote osteoclast recruitment, differentiation, and prolonged survival, whereas others (eg, IL-7) inhibit osteoblast differentiation and activity and cause premature death of osteoblasts (a process known as apoptosis). 24-27 This has led some to refer to postmenopausal osteoporosis as an inflammatory autoimmune disease triggered by estrogen deficiency.23 Though treatment with estrogen can reverse the inflammatory processes in bone, researchers are looking for new agents that can mimic the salutary effects of estrogen on bone without inducing the negative effects on organs such as the breast and heart.
O T H ER F A C T O R S A number of other factors implicated in the pathogenesis of osteoporosis that are beyond the scope of this article include the following: polymorphisms in the vitamin D receptor and other relevant genes; alterations in local and systemic growth factors, such as insulin-like growth factor-1 and bone morphogenic protein; effects of cytokines, prostaglandins, nitrous oxide, and leukotrienes; collagen abnormalities and elevations in homocysteine; and the influence of leptin and neural inputs from the sympathetic nervous system on bonefl CLINICAL
MANIFESTATIONS
Osteoporosis is generally a silent disease until a fragility fracture occurs. 39 The annual incidence of osteoporotic fractures exceeds 1.5 million in the United States.4° Among white women aged _>50years, -40% will experience a hip, spine, or wrist fracture during the remainder of their lives.41 Hip fractures, the most devastating type of osteoporotic fracture, are projected to increase from an estimated 1.7 million in 1990 to 6.3 million by the year 2050.42 Notably, 20% of patients die during the first year after a hip fracture, 43 nearly one third require nursing home placement after hospital discharge, and fewer than one third regain their prefracture level of physical functioning. 3,~ Vertebral fractures are associated with increased morbidity (back pain, height loss, deformity, and disability) and mortality.45 49 Among postmenopausal women who sustain a new vertebral fracture, 1 in 5 will experience another vertebral fracture in the next year. 5° Multiple thoracic fractures can result in restrictive lung disease, 51 progressive back pain, and disabling kyphosis. Other sequelae include constipation, abdominal pain and distention, reduced appetite, premature satiety, and weight loss. 52 The pain, physical limitations, and changes in lifestyle and appearance caused by osteoporotic fractures can have damaging psychological effects, including depression, loss of self-esteem, anxiety, fear, anger, and
C A L C I U M , V I T A M I N D, A N D PARATHYROI D H O R M O N E Particularly among the elderly, insufficient calcium intake, impaired intestinal absorption of calcium due to aging or disease, and deficiency of vitamin D can result in secondary hyperparathyroidism and bone loss. 28 Vitamin D deficiency and secondary hyperparathyroidism are extremely common among elderly patients admitted to hospitals with fragility fractures 29 and undoubtedly contribute to accelerated bone loss and increasing skeletal fragility, as well as to neuromuscular weakness that can increase the risk of falls.3°-32 Clinical trials involving older individuals at high risk for calcium and vitamin D deficiency indicate that supplementation of both can reverse secondary hyperparathyroidism, decrease bone resorption, increase bone mass, reduce fracture rates, and even decrease the frequency of fallsfl8'33'34 However, in some recent large studies, calcium and vitamin D supplementation did not reduce fracture incidence significantly, perhaps because the populations studied were less deficient in calcium and/or vitamin D than other populations studied. 35,36
22
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10. Howard GM, Nguyen TV, Harris M, et al. Genetic and environmental contributions to the association between quantitative ultrasound and bone mineral density measurements: A twin study. J Bone Miner Res. 1998;13: 1318-1327. 11. Stewart A, Kumar V, Reid DM. Long-term fracture prediction by DXA and Q U S - - a 10-year prospective study. J Bone Miner Res. 2006;21:413-418. 12. Pantsulaia I, Trofimov S, Kobyliansky E, Livshits G. Contribution of the familial and genetic factors on monocyte chemoattractant protein- 1 variation in healthy human pedigrees. Cytokine. 2005;32:117-123. 13. Khosla S, Riggs BL, Atkinson EJ, et al. Effects of sex and age on bone microstructure at the ultradistal radius: A population-based noninvasive in vivo assessment. J Bone Miner Res. 2006;21:124-131. 14. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664. 15. Khosla, S. Minireview: The OPG/RANKL/RANK system. Endocrinology. 2001; 142:5050-5055. 16. McClung MR, Leweicki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821-831. 17. Garnero R Sornay-Rendu E, Chapuy MC, Delmas PD. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J Bone Miner Res. 1996;11:337-349. 18. Parfitt AM, Villanueva AR, Foldes J, Rao DS. Relations between histologic indices of bone formation: Implications for the pathogenesis of spinal osteoporosis. J Bone Miner Res. 1995;10:466-473. 19. Ebeling PR, Atley LM, Guthrie JR, et al. Bone turnover markers and bone density across the menopausal transition. J Clin Endocrinol Metab. 1996;81:3366-3371. 20. Riggs BL, Khosla S, Melton LJ III. Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev. 2002;23:279-302. 21. Goderie-Plomp HW, van der Klift M, de Ronde W, et al. Endogenous sex hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: The Rotterdam Study. J Clin Endocrinol Metab. 2004;89:3261-3269. 22. Van Pottelbergh I, Goemaere S, Kaufman JM. Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age. J Clin Endocrinol Metab. 2003;88: 3075-3081. 23. Weitzmann MN, Pacific R. Estrogen deficiency and bone loss: An inflammatory tale. J Clin Invest. 2006;116:11861194. 24. Weitzmann MN, Pacifici R. The role of T lymphocytes in bone metabolism. Immunol Rev. 2005;208:154-168. 25. Weitzmann MN, Roggia C, Toraldo G, et al. Increased production of IL-7 uncouples bone formation from bone resorption during estrogen deficiency. J Clin Invest. 2002;110:1643-1650. 26. Gilbert L, He X, Farmer R et al. Inhibition of osteoblast differentiation by tumor necrosis factor-alpha. Endocrinology. 2000;141:3956-3964.
strained relationships with family and friends.53 55 These adverse physical and psychological outcomes following an osteoporotic fracture can precipitate social isolation, physical deterioration, and worsening frailty,
KEY
•
POINT
Osteoporotic fractures cause serious physical and psychological sequelae.
SUMMARY We have come a long way in our understanding of osteoporosis in the 66 years since Fuller Albright first described the disease in postmenopausal women. The pathogenesis of osteoporosis is complicated and multifaceted, involving genetics, cellular immunity, inflam-
mation, and complex systems of hormonal signaling and regulation. Over time, insights into these basic mechanisms should greatly improve our care of patients with osteoporotic fractures and help prevent fractures in those at greatest risk,
REFERENCES 1. Albright F, Bloomberg E, Smith PH. Postmenopausal osteoporosis. Trans Assoc Am Physicians. 1940;55: 298305. 2. Raisz L. Pathogenesis of osteoporosis: Concepts, conflicts, and prospects. J Clin Invest. 2005;115:3318-3325. 3. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. ,lAMA. 2001;285:785-795. 4. Felsenberg D, Boonen S. The bone quality framework: Determinants of bone strength and their interrelationships, and implications for osteoporosis management. Clin Ther 2005;27:1-11. 5. Seeman E, Delmas PD. Bone quality--the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354:2250-2261. 6. Mora S, Gilsanz V. Establishment of peak bone mass. Endocrinol Metab Clin North Am. 2003;32:39-63. 7. Walker MD, Babbar R, Opotowsky AR, et al. A referent bone mineral density database for Chinese American women. Osteoporos Int. 2006;17:878-887. 8. Seeman E. Sexual dimorphism in skeletal size, density, and strength. J Clin Endocrinol Metab. 2001;86:45764584. 9. Sambrook PN, Kelly PJ, Morrison NA, et al. Scientific review. Genetics of osteoporosis. Br J Rheumatol. 1994; 33:1007-1011. 23
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27. Cenci S, Weitzmann MN, Roggia C, et al. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-c~. J Clin Invest. 2000;106:1229-1237. 28. Lips R Vitamin D deficiency and secondary hyperparathyroidism in the elderly: Consequences for bone loss and fractures and therapeutic implications. Endocr Rev. 2001; 22:477-501. 29. Becker C, Crow S, Toman J, et al. Characteristics of elderly patients admitted to an urban tertiary care hospital with osteoporotic fractures: Correlations with risk factors, fracture type, gender and ethnicity. Osteoporos Int. 2006; 17:410-416. 30. Boonen S, Bischoff-Ferrari HA, Cooper C, et al. Addressing the musculoskeletal components of fracture risk with calcium and vitamin D: A review of the evidence. Calcif Tissue Int. 2006;78:257-270. 31. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC, et al. Effect of vitamin D on falls: A meta-analysis. JAMA. 2004;291:1999-2006. 32. Sambrook PN, Chen JS, March LM, et al. Serum parathyroid hormone predicts time to fall independent of vitamin D status in a frail elderly population. J Clin Endocrinol Metab. 2004;89:1572-1576. 33. Bischoff-Ferrari HA, Orav EJ, Dawson-Hughes B. Effect of cholecalciferol plus calcium on falling in ambulatory older men and women: A 3-year randomized controlled trial. Arch Intern Med. 2006;166:424-430. 34. Bischoff HA, Stahelin HB, Dick W, et al. Effects of vitamin D and calcium supplementation on falls: A randomized controlled trial. J Bone Miner Res. 2003; 18:343-351. 35. Grant AM, Avenell A, Campbell MK, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): A randomised placebocontrolled trial. Lancet. 2005;365:1621-1628. 36. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683. 37. Lips R Which circulating level of 25-hydroxyvitamin D is appropriate? J Steroid Biochem Mol Biol. 2004;89-90: 611-614. 38. Pasco JA, Henry MJ, Kotowica MA, et al. Seasonal periodicity of serum vitamin D and parathyroid hormone, bone resorption, and fractures: The Geelong Osteoporosis Study. J Bone Miner Res. 2004; 19:752-758. 39. National Osteoporosis Foundation. Physician's guide to prevention and treatment of osteoporosis. Available at: http ://www'n° f'°rg/-vti-birdshtml'dll/physguide/index'htm" Accessed October 1, 2006. 40. National Osteoporosis Foundation. America's Bone Health: The State o f Osteoporosis and Low Bone Mass in Our Nation. Washington, DC: National Osteoporosis Foundation; 2002.
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41. US Dept of Health and Human Services. Bone Health and Osteoporosis: A Report o f the Surgeon General. Rockville, MD: US Dept of Health and Human Services, Public Health Service, Office of the Surgeon General; 2004. 42. Cummings SR, Melton LJ III. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359:1761-1767. 43. National Institutes of Health. Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement. 2000;17: 1-45. 44. Empana JR Dargent-Molina R Breart G, and the EPIDOS Group. Effect of hip fracture on mortality in elderly women: The EPIDOS prospective study. J Am Geriatr Soc. 2004;52:685-690. 45. Ensrud E, Thompson DE, Cauley JA, et al, and the Fracture Intervention Trial Research Group. Prevalent vertebral deformities predict mortality and hospitalization in older women with low bone mass. J A m Geriatr Soc. 2000; 48:241-249. 46. Kado DM, Browner WS, Palermo L, et al, and the Study of Osteoporotic Fractures Research Group. Vertebral fractures and mortality in older women: A prospective study. Arch Intern Med. 1999;159:1215-1220. 47. Nevitt MC, Ettinger B, Black DM, et al. The association of radiographically detected vertebral fractures with back pain and function: A prospective study. Ann Intern Med. 1998;128:793-800. 48. Johnell O, Kanis JA, Oden A, et al. Mortality after osteoporotic fractures. Osteoporos Int. 2004; 15:38-42. 49. Miyakoshi M, Itoi E, Kobayashi M, Kodama H. Impact of postural deformities and spinal mobility on quality of life in postmenopausal osteoporosis. Osteoporos Int. 2003; 14: 1007-1012. 50. Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA. 2001;285:320-323. 51. Lombardi I, Oliveira LM, Mayer AF, et al. Evaluation of pulmonary function and quality of life in women with osteoporosis. Osteoporos Int. 2005;16:1247-1253. 52. Lane NE. Epidemiology, etiology and diagnosis of osteoporosis. Am J Obstet Gynecol. 2006;194(Suppl 1):$3Sll. 53. Gold DT. The nonskeletal consequences of osteoporotic fractures. Psychologic and social outcomes. Rheum Dis' Clin North Am. 2001;27:255-262. 54. Adachi JD, Ioannidis G, Olszynski WR et al. The impact of incident vertebral and non-vertebral fractures on health related quality of life in postmenopausal women. BMC Musculoskelet Disord. 2002;3:11. 55. Johnell O, Kanis J. Epidemiology of osteoporotic fractures. Osteoporos Int. 2005;16(Suppl 2):$3-$7.
Address correspondence to: Carolyn Becker, MD, Toni Stabile Osteoporosis Center, Columbia University, 180 Fort Washington Avenue, Harkness Pavillion, Room 904, New York, NY 10032. E-mail: [email protected] 24
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Dialogue Box EDITORIAL
BOARD
Do osteocytes retain the ability to differentiate into osteoclasts and osteoblasts?
EDITORIAL
BOARD
How do estradiol levels compare in men versus women?
BECKER
BECKER
No, osteoclasts and osteoblasts do not come from osteo-
Surprisingly, it turns out that postmenopausal women
cytes. Instead, they are derived from hematopoietic pre-
have lower estradiol levels than men. The average serum
cursors and mesenchymal stem cells, respectively. Osteo-
estradiol level in men can range from 25 to 50 pg/mL,
cytes are senescent osteoblasts imbedded in the bone
whereas in women it often falls well below 20 pg/mL.
matrix. EDITORIAL B O A R D EDITORIAL B O A R D
Is estrogen more important than testosterone in
Although senescent, don't osteocytes play an impor-
maintaining bone integrity in men?
tant role in maintaining bone strength? BECKER
BECKER
Yes, and estrogen plays a critical role throughout the
Yes. We used to think the osteocytes were dormant and
life cycle of men. During puberty, estradiol is needed
not doing much. It turns out they are absolutely critical
for maturation of the male skeleton and closure of
for the health of the bone. Osteocytes are responsible
the epiphyses. After maturity, estrogen appears more
for sensing the mechanical stresses and structural
important than testosterone in maintaining bone min-
demands on the skeleton and detecting areas of micro-
eral density (BMD). This has been demonstrated in
damage. Once a microcrack in the bone is detected, using an intricate cell-to-cell communications network, osteocytes are able to recruit osteoclasts and osteoblasts to the areas where bone remodeling needs to occur. Avascular necrosis results from the death of osteocytes. Osteocyte apoptosis is also found in osteonecrosis of the jaw due to bisphosphonate therapy. EDITORIAL B O A R D What is the mechanism for osteoporosis occurring in patients with hyperthyroidism?
elegant studies of men given gonadotropin-releasing hormone agonists that shut off pituitary gonadotrophs and cause a fall in testosterone production. If you selectively give these subjects either testosterone coupled with an aromatase inhibitor (which prevents testosterone conversion to estrogen) or estrogen alone, it turns out the estrogen is more effective in preventing bone loss than testosterone. Large epidemiologic studies have also found that although bone loss, osteoporosis, and fractures in men do not correlate well with testosterone levels, a strong correlation
BECKER
exists with estradiol levels. An event that really revo-
Basically any process that accelerates bone turnover
lutionized this field occurred about 10 years ago with
in adults, whether hyperthyroidism, postmenopausal
the report of a young man with open epiphyses, linear
estrogen deficiency, or hyperparathyroidism, results in
growth well into his late 20s, and significant osteo-
increased bone resorption. In adults, this leads to bone
porosis. This young man had a mutation in the aro-
loss because the time needed for osteoclasts to resorb
matase gene that caused him to have plenty of testos-
bone is much shorter than the time needed by
terone in his body but no estrogen. Treatment of this
osteoblasts to fill in the bone. So, there is a net loss of
young man with estrogen produced an increase in
bone in all cases of high bone turnover.
bone density and fusion of his epiphyses.
25
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Vol. 8, No. 1
Dialogue Box EDITORIAL
is more important. However, in patients with chron-
BOARD
Does this mean that with regard to osteoporosis, the
ic obstructive pulmonary disease, there have been
efficacy of testosterone replacement is dependent on
some nice studies comparing supplementation with
its conversion to estrogen?
25-hydroxyvitamin D versus 1,25-dihydroxyvitamin D.
BECKER
more efficacious in improving BMD and preventing
In these patients, the 1,25-dihydroxyvitamin D was Yes, in part. Perhaps 60% to 70% is an estrogen effect
fractures than 25-hydroxyvitamin D. For most elderly
and the remainder is an independent testosterone effect.
patients, however, we really focus on keeping the
So both estrogen and testosterone are important for the
25-hydroxyvitamin D level above 30 ng/mL.
male skeleton. EDITORIAL EDITORIAL
BOARD
What agents are available for stimulating osteoblast
BOARD
Can you explain the mechanism by which vitamin D
activity?
supplementation reduces the risk of falls? BECKER
Although continuous exposure to parathyroid hormone
BECKER
Vitamin D is my favorite hormone since it has multiple
(PTH), as in primary or secondary hyperparathyroidism,
beneficial properties. Vitamin D has a direct effect on
turns on the receptor activator of nuclear factor-~zB
myocytes and muscle fibers, in addition to its effects on
ligand system and causes increased bone resorption,
bone. A number of studies have looked at fall risk inde-
PTH administered in an intermittent manner (as with
pendent of bone density and found that if you take a
teriparatide), activates a totally different biochemical
group of people from a nursing home and you put half
pathway that stimulates osteoblasts. Other osteoblast-
of them on calcium alone and the other half on calcium
activating agents include growth hormone, insulin growth
and vitamin D, you will find significantly fewer falls in
factor-l, and strontium ranelate, which is available in
the latter group within 3 months. Physiologic testing
Europe. Interestingly, if you could develop a statin that
has demonstrated improved muscle strength, gait, and
went predominantly to the bone instead of to the liver,
reduced body sway simply by repleting vitamin D in
it would be anabolic.
patients deficient in this vitamin. In addition to direct effects on muscle and bone, vitamin D may favorably
EDITORIAL
impact the immune system and offer antitumor effects
Since the age at which peak BMD is achieved
as well.
appears genetically programmed, if for some reason
BOARD
there is a delay in achieving peak BMD, is there a EDITORIAL
period of "catch-up"?
BOARD
Is the deficiency with 1,25-dihydroxyvitamin D or with 25-hydroxyvitamin D?
BECKER
To a certain extent it depends on how early the delay BECKER
occurs--for example, if a young woman has a year of
That's a good question. It turns out that you can have total-
anorexia nervosa in her early teens but then has full
ly normal 1,25-dihydroxyvitamin D levels in the setting of
nutritional and hormonal recovery, there may be nearly
deficient 25-hydroxyvitamin D and still have osteomala-
total catch-up growth in BMD. But if she misses that
cia, increased fall risk, and muscle weakness. So you need
critical window of time--for most Caucasian women in
both. For muscle and bone, we think 25-hydroxyvitamin D
their 20s--once the window closes, it closes. After that,
26
Clinical Cornerstone
•
MANAGEMENT
OF O S T E O P O R O S I S
•
Vol. 8, No. 1
Dialogue Box even if the eating disorder, amenorrhea, or other sec-
amounts of calcium and vitamin D, to exercise, and to
ondary disorder is cured, the BMD will never get any
refrain from smoking. In addition, it is prudent for
higher than it was at the time of her genetically pro-
women to avoid using it for a prolonged period of time
grammed attainment of peak bone mass. That's why I
since it may prevent achievement of optimal peak
emphasize that osteoporosis is really a pediatric disease
BMD.
that presents in adulthood. The peak bone mass you accrue during childhood, adolescence, and young adult-
EDITORIAL BOARD
hood is the maximum you can achieve.
Is there any value to getting a dual energy x-ray a b s o r p t i o m e t r y (DXA) scan on a w o m a n on Depo-
EDITORIAL BOARD
Provera?
W h a t happens in the lactating female? BECKER BECKER
In a patient you deem at risk for osteoporosis based on
During lactation, women can lose a tremendous amount
other risk factors (such as family history, body build,
of bone. However, breastfeeding is not a risk factor for
cigarette use, or ethnicity), it's probably reasonable to
future fractures since rapid reversal of bone loss occurs
get a DXA scan. If the BMD is very low, you may want
after lactation ends.
to advise the young woman to find an alternative form of birth control.
EDITORIAL BOARD What's the current thinking with the risk associated
EDITORIAL BOARD
with depot m e d r o x y p r o g e s t e r o n e
What value on a DXA scan would be cause for
acetate (Depo-
Provera ® [Pharmacia & Upjohn, N.V/S.A., Puurs,
concern?
Belgium])? BECKER
BECKER
A Z-score of <2 SDs and certainly a Z-score <2.5 SDs
Depo-Provera clearly leads to lower BMD and bone loss
below age-matched women would be cause for concern.
due to reduced levels of estrogen. The bone loss is most
Even in a young woman with a Z-score of <2.5 SDs,
acute during the first 1 to 2 years of use and then it tends
however, I would not use the term "osteoporosis." Instead,
to slow down as a new equilibrium is reached. Once
I would tell her she has a BMD that is significantly below
Depo-Provera is discontinued, there is nearly complete
her peers and that by stopping Depo-Provera she could
recovery of BMD. The skeletal risk from Depo-Provera
improve her BMD. This recommendation has to be
depends on the duration of use and the age when it is
weighed against the risks and benefits of other forms of
started. It has not been definitively shown, however, to
birth control since preventing an unwanted pregnancy
be a risk factor for fractures. Young women who use
may take priority over the adverse skeletal effects from
Depo-Provera should be counseled to take in adequate
Depo-Provera.
27