As the most common bone disease in

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1 AN UPDATE ON OSTEOPOROSIS EPIDEMIOLOGY AND BONE PHYSIOLOGY Elena M. Umland, PharmD* ABSTRACT Osteoporosis is a significant public health concern, affecting 10 million Americans over the age of 50 and causing fractures in 1.5 million patients annually. Although achievement of peak bone mass has always been considered of extreme importance, bone mineral density (BMD) alone does not predict fracture risk, and as such, experts recommend using a fracture prediction algorithm that takes into account femoral neck BMD and identified clinical risk factors. This article focuses on the epidemiology and pathophysiology of osteoporosis, with a discussion on the role of the endocrine system and the receptor activator of nuclear factor-κb (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway in bone remodeling. RANK/RANKL/OPG is a signal transduction pathway that appears to be the molecular mechanism by which osteoblasts and osteoclasts function in a coordinated fashion at the basic multicellular unit. Endocrine components that are discussed as having a skeletal influence include estrogen, parathyroid hormone, growth hormone, insulin-like growth factor-1, thyroid hormone, and cortisol. (Adv Stud Pharm. 2008;5(7): ) *Associate Dean for Academic Affairs, Jefferson College of Health Professions, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, Pennsylvania. Address correspondence to: Elena M. Umland, PharmD, Associate Dean for Academic Affairs, Jefferson College of Health Professions, Jefferson School of Pharmacy, Thomas Jefferson University, 130 South 9th Street, Philadelphia, PA Elena.umland@jefferson.edu. As the most common bone disease in humans, osteoporosis is steadily increasing in prevalence due to a growing elderly population and, thus, represents a major public health concern. 1 This skeletal disorder is characterized by several pathologic events (ie, low bone mass, deterioration of bone tissue, disruption of bone architecture, and reduced bone strength), all of which increase the risk for fractures. 1,2 Based on the World Health Organization (WHO) diagnostic criteria, o s t e o p o rosis is defined by bone mineral density (BMD) at the hip or spine that is less than or equal to 2.5 standard deviations (SDs) below the young normal mean reference population (T-score). 1 Dual-energy X- ray absorptiometry (DXA) at the spine or hip is the gold-standard test for measuring central BMD (see Table 1 for T-scores corresponding to various levels of bone health). 1,2 A decrease of 1 SD correlates to an approximate 10% to 12% decrease in BMD and an increase in fracture risk by a factor of 1.5 to For every 1 SD decline in spine BMD, the risk of spine fracture increases 2.3-fold and the risk of hip fracture increases 2.6-fold. 2 EPIDEMIOLOGY Based on the 2004 Surgeon General s report, an estimated 10 million Americans over the age of 50 have osteoporosis of the hip, 34 million have osteopenia, and 1.5 million suffer from an osteoporosis-related fracture annually. 3 These statistics contribute to more than hospitalizations, over emergency department visits, more than 2.6 million physician visits, and the placement of patients into nursing homes annually in the United States. 3 Fractures, most commonly those of the vertebrae (spine), proximal femur (hip), and distal forearm (wrist), are the most relevant clinical sequelae of osteoporosis. 1 Complications of fractures, particularly in the 210 Vol. 5, No. 7 October 2008

2 Table 1. T-Score and the Definition of Bone Health Normal bone mineral density T-score at or above -1 Osteopenia T-score of -1.1 to -2.4 Osteoporosis T-score at or below -2.5 Reprinted with permission from Menopause. 2006;13: elderly, include increased mortality (with hip and vertebral fractures) and morbidity, which manifests as significant pain, loss of ability to perform activities of daily living or to ambulate, and an increased risk of developing pressure sores, pneumonia, and urinary tract infections. Osteoporosis and its resultant fractures may also contribute to the development of a negative body image, reduced self-esteem, and declining mood. 3 Fracture-related statistics are quire alarming, with the total lifetime risk for sustaining a fracture of the hip, spine, or wrist being approximately 40% for women and 13% for men. 4 Worldwide, there was an estimated 1.66 million hip fractures in As a result of the increasing number of elderly patients, the Surgeon General estimates that the number of hip fractures and their associated costs may increase by 50% in 2025 and may double or triple by the year 2040, with the number of hip fractures potentially reaching 6.3 million by the year ,5 Hip fractures occur, on average, at age 82 and are generally associated with a 10% to 20% increase in mortality (especially in the elderly), as well as recurrence, within the first year. 3 Up to 25% of patents with hip fractures may require long-term care, and only 40% fully regain their prefracture level of independence. 1 Although osteoporosis is often viewed as a disease affecting women, it is also known to significantly affect men. Using male-specific cutoffs, 6% of US men over 50 years of age have osteoporosis and 47% have osteopenia, versus 18% and 50% of women, respectively. 6 Almost 50% of all hip fractures in men occur before the age of 80, and 33% of worldwide hip fractures occur in men. 6 Furthermore, although more women than men are affected by this disease, more men than women are actually known to die in the year following a hip fracture. From an economic perspective, the direct costs associated with fractures ranged from $12.2 to $17.9 billion in 2002, with indirect costs likely adding billions of dollars to this figure. 3 In a recent 2008 publication focusing on the epidemiology of osteoporosis, the combined annual costs of all osteoporosis-related fractures in the United States was estimated to be $20 billion. 5 Overall, hip fractures account for approximately 72% of these fracture-related costs. 1 GENERAL BONE HEALTH AND RISK FACTORS The foundation of optimal bone health lies in attaining the greatest peak bone mass possible. Ac h i e ved by the age of 25 to 30 years, peak bone mass is determined largely by genetic factors, although other impacting factors (ie, nutrition, endocrine status, physical activity, and health during growth) also play a ro l e. 4 For all patients, both young and old, the recommendations for achieving and maintaining optimal bone health include receiving the appro p r i a t e amount of calcium and vitamin D, performing re g u- lar weight-bearing exe rcise, avoiding or minimizing alcohol use, and being aware of, and employing, fall p re vention strategies. And although achieving peak bone mass is of e x t rem e importance, BMD alone does not pre d i c t f r a c t u re risk, as evidenced by data showing that fract u res still occur in the absence of W H O - d e f i n e d o s t e o p o ro s i s. 4 Of women aged 65 or older, 40% of those with hip fractures have osteopenia (not osteop o rosis), and 74% of those with nonve rtebral fract u res have T- s c o res that are higher than the cutoff values for defining osteoporosis (greater than -2.5). 4 In one study, re s e a rchers observed that of patients with normal T- s c o res, 16.1% had evidence of a prior ve rtebral fracture, and of those, 26.3% had multiple prior fracture s. 5 These data are further supported by the W H O, which has stated that DXA, by itself, is not optimal for detecting patients at high risk for fractures. DXA is considered to have high specificity; meaning that the risk of fracture is high when osteoporosis by T- s c o re definition is present. Howe ve r, DXA possesses l ow sensitivity; meaning that fracture risk is not, nece s s a r i l y, negligible when BMD is normal. 7 T h e re f o re, in response to the growing body of evidence indicating that BMD alone is not sufficient in determining f r a c t u re risk, the WHO has developed an algorithm that takes into account femoral neck BMD and specific clinical risk factors (Table 2) to identify an indiv i d u a l s 10-year probability of a hip fracture and any University of Tennessee Advanced Studies in Pharmacy 211

3 Table 2. Risk Factors Assessed in Determining F r a c t u re Risk Femoral neck bone mineral density Prior fragility fracture Glucocorticoid exposure Age Parental history of (hip) fracture Smoking Excessive intake of alcohol Rheumatoid arthritis Low body mass index Data from World Health Organization. 7 other major osteoporotic fracture (see article by Christina Barrington, PharmD, for more information on the WHO fracture risk algorithm). 1, 7 In general, it is imperative that conditions and medications contributing to osteoporosis (Tables 3 and 4) and risk factors employed in estimating fracture risk (Table 2) be observe d. 1, 8 THE BONE REMODELING PROCESS Along with availability of evidence-based tools that s u p p o rt healthcare providers in making more informed decisions re g a rding osteoporosis management, re s e a rc h p roviding greater insight into the process of bone remodeling has increased substantially. Overall, bone remodeling replaces approximately 5% to 10% of the adult human skeleton annually, and aids in the maintenance of a healthy skeleton by continually removing older bone and replacing it with newer bone. 1,9 Osteoblasts (cells responsible for bone formation) and osteoclasts (cells responsible for bone resorption or the breakdown of bone) compose the basic multicellular unit (BMU), which is where bone remodeling and reconstruction occur. 10 Within each BMU, the process of bone resorption takes approximately 3 weeks (per site), whereas bone remodeling and refilling of lost bone may take up to 3 to 4 m o n t h s. 9 Osteocytes, cells derived from senescent osteoblasts, direct when and where bone remodeling will occur. 10 Imbalances in this normal remodeling process (as a result of menopause and conditions noted in Table 3) lead to greater bone removal than replacement, and subsequently to a reduction in BMD, the Table 3. Common Conditions Associated with S e c o n d a ry Osteoporosis Condition Anorexia nervosa Diabetes mellitus type 1 Malignancy Organ transplantation Rheumatoid arthritis Chronic obstructive pulmonary disease Chronic renal disease Cause or Mechanism Malnutrition, amenorrhea (estrogen deficiency), or excess endogenous cortisol Decreased bone formation, impaired IGF-1, excessive renal calcium loss, or secondary hyperparathyroidism Aggressive chemotherapy, long-term highdose glucocorticoid treatment, irradiation, poor nutrition, or underlying illness (may affect bone-cell function) Chemotherapy, glucocorticoid use, or immunosuppressive therapy Glucocorticoid therapy or decreased mobility Reduced lung function, smoking, glucocorticoid use, low BMI, or immobility due to dyspnea Impaired vitamin D hydroxylation or secondary hyperparathyroidism BMI = body mass index; IGF = insulin-like growth factor. Data from Hansen and Vondracek. 8 Table 4. Medications Associated with Osteoporo s i s Medication(s) or Treatment Cause or Mechanism Anticonvulsants Cyclosporine Glucocorticoid use (long-term) Stimulation of bone resorption and sup- pression of osteoblast function Heparin (high dosage and long duration) Irradiation Methotrexate Tacrolimus Thyroid hormone Warfarin Increased bone turnover, increased metabolism and clearance of vitamin D, hypocalcemia, or hypophosphatemia Increased bone turnover and bone loss in animals Impaired bone formation, increased bone resorption, decreased calcium absorption, increased calcium excretion, or oral and possibly inhaled glucocorticoids Direct detrimental effects on bone or pituitary hormone deficiencies from cranial irradiation Dose-dependent bone loss or increase in bone resorption and inhibition of bone formation Increased bone loss in animals Increased bone turnover and resorption Low vitamin K level leading to impaired bone formation* *Mechanism is controversial. Reprinted with permission from Hansen and Vondracek. Am J Health Syst Pharm. 2004;61: Vol. 5, No. 7 October 2008

4 development of osteoporosis and, ultimately, fractures. 1 Many neighboring organ systems, associated hormones, and underlying molecular processes contribute to normal bone remodeling and pathophysiologic skeletal alterations. RANK/RANKL/OPG PATHWAY This signal transduction pathway appears to be the molecular mechanism by which osteoblasts and osteoclasts function in a coordinated fashion at the BMU. 10 Receptor activator of nuclear factor-κb (RANK) is a type I homotrimeric transmembrane protein that is e x p ressed widely on normal cells and on the surface of osteoclasts and osteoclast pre c u r s o r s. 10 Ac t i va t i n g mutations of RANK has resulted in increased osteoclast formation and activity. 11 RANK ligand (RANKL) is a type II homotrimeric transmembrane p rotein that is synthesized by osteoblasts, bone marrow stromal cells, and activated T cells. 10, 12 Ex p re s s e d both as a membrane-bound and a secreted pro t e i n, RANKL stimulates the release of immature osteoclast p rogenitors into the circulation and binds to osteop rotegerin (OPG), a soluble decoy re c e p t o r. 10, 11 T h e binding of RANKL to RANK results in differe n t i a- tion of osteoclast precursors into mature, functional osteoclasts, in addition to direct activation of alre a d y m a t u re osteoclasts. 10 Osteoprotegerin, a soluble member of the tumor necrosis factor (TNF) receptor family, is expressed on osteoblasts and in bone marrow (among many other tissues), and is a very effective inhibitor of osteoclast formation. 9,11 The OPG protein, however, is unstable and difficult to obtain because it undergoes rapid degradation in vivo. 12 The binding of RANKL to the decoy receptor OPG avoids RANK-RANKL interaction and, therefore, inhibits resorption, because the differentiation of osteoclast precursors into mature osteoclasts and direct activation of mature osteoclasts are not prompted to occur. Thus essentially, blockade of the RANK/RANKL signal pathway leads to inhibition in the formation and differentiation of osteoclasts, and the resultant bone resorption process that follows. 12 Osteoblast expression of RANKL and OPG influences bone resorption and, generally, upregulation of RANKL expression by cytokines and growth factors is associated with relative downregulation of OPG (see article by Mary Beth O Connell, PharmD, BCPS, FASHP, FCCP, on therapeutic applicability of the RANK/RANKL/OPG pathway). 11 ENDOCRINE INFLUENCES The sex hormones estrogen and testostero n e, which are vital in regulating skeletal growth and maintaining bone mass and strength, have effects in both men and women. Testosterone has direct anabolic effects on bone and is a source of estrogen, because it is converted to estrogen in fat cells. 3 Functional estrogen receptors are expressed on osteoblasts, osteoclasts, and osteocytes. 10 These receptors are also expressed on bone marrow stromal cells, which provide physical support for future osteoclasts, T cells, B cells, and many other bone marrow cells. 10 Estrogen deficiency causes T cells to release a variety of inflammatory cytokines that have various actions. For example, interleukin (IL)-1, IL-6, and TNF-α promote osteoclast recruitment, differentiation, and prolonged survival. IL-7 inhibits osteoblast differentiation and activity, causing apoptosis of osteoblasts. Menopausal estrogen decline leads to a large, sudden, increase in the osteoclast population and pro l o n- gation of their life span. 13 And because estro g e n lengthens the working lives of osetoblasts by suppre s s- ing cell apoptosis, a drop in estrogen also results in loss of osteoblast pro d u c t i v i t y. 13 In addition, nongenomic e s t rogen receptors on the surface of intestinal epithelial cells help drive calcium into the cells, thus a decline in e s t rogen may reduce intestinal calcium uptake. 13 Pa r a t h y roid hormone (PTH) acts on the kidney to c o n s e rve calcium and to stimulate calcitriol pro d u c t i o n, which increases intestinal absorption of calcium. 3 P T H also acts on the skeleton to increase movement of calcium from blood to bone. PTH-activated re c e p t o r s reduce osteoblast apoptosis when stimulated, leading to an increase in the working lives of osteoblasts and subs e q u e n t l y, to increased bone formation. 13 PTH also has i n d i rect anabolic effects through regulation of other bone-forming skeletal growth factors (eg, insulin-like g rowth factor-1 [IGF-1]) and growth factor antagonists (eg, sclero s t i n ). 14 PTH levels begin to decline when the c i rculating form of vitamin D falls below 30 ng/ml. 10 Other endocrine hormones that influence the skeleton include growth hormone (GH), thyroid hormone (TH), and cortisol. De r i ved from the pituitary gland, GH accelerates skeletal growth at puberty and stimulates production of IGF-1, which exe rts direct action on osteoblasts and is necessary for skeletal deve l o p m e n t and maintenance of bone mass. 3, 14 De c reased pro d u c- tion of GH and IGF-1 with advancing age may be partially responsible for the impaired ability of older University of Tennessee Advanced Studies in Pharmacy 213

5 individuals to form bone or to replace lost bone. 3 T H i n c reases the energy-carrying capacity of all cells (including bone cells), and there f o re, it increases the rate of bone formation and resorption. W h e reas TH deficiency can impair growth in children, TH excess may incre a s e bone resorption, weakening the skeleton. 3 C o rtisol, the major hormone of the adrenal gland, has complex effects on the skeleton, with small amounts being necessary for normal bone development and exc e s s i ve amounts blocking bone growth. To this point, long-term use of glucoc o rticoids decreases bone formation and increases bone resorption, and is there f o re, considered a major contributor to secondary osteoporo s i s. 3 GENETIC FACTORS Also a significant influence on bone remodeling, genetic variants may impact bone strength. Sequence variants that are significantly associated with BMD have been identified in 5 genomic regions; 3 of these regions are close to or within: (1) the RANKL gene ( c h romosomal location, 13 q14); (2) OPG gene (8q24); and (3) the estrogen receptor-1 gene (6q25). 15 These 3 chromosomal locations appear to influence BMD at both the spine and hip. When tested for associations between low-trauma fracture and the singlenucleotide polymorphisms associated with BMD, the 8q24 locus was associated with all categories of fractures and the 18q21 locus (RANK) was associated with low-trauma fractures. 15 CONCLUSIONS Many physiologic factors are responsible for maintaining a healthy skeleton, as well as contributing to pathologic bone states, such as osteoporo s i s. An understanding of the normal bone re m o d e l i n g p rocess and the various factors that may affect the balance between bone formation and bone resorption is critical to the optimal management of osteoporo s i s. REFERENCES 1. National Osteoporosis Foundation. Clinician s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society. Menopause. 2006;13: US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, Office of the Surgeon General; Lane JM, Serota AC, Raphael B. Osteoporosis: differences and similarities in male and female patients. Orthop Clin North Am. 2006;37: Cole ZA, Dennison EM, Cooper C. Osteoporosis epidemiology update. Curr Rheumatol Rep. 2008;10: Ebeling PR. Osteoporosis in men. N Engl J Med. 2008;358: World Health Organization. WHO Scientific Group on the Assessment of Osteoporosis at Primary Health Care Level. Geneva, Switzerland: WHO Press, World Health Organization; Hansen LB, Vondracek SF. Prevention and treatment of nonpostmenopausal osteoporosis. Am J Health Syst Pharm. 2004;61: Martin TJ, Seeman E. New mechanisms and targets in the treatment of bone fragility. Clin Sci. 2007;112: Becker C. Pathophysiology and clinical manifestations of osteoporosis. Clin Cornerstone. 2006;8: Boyce BF, Xing L. The RANKL/RANK/OPG pathway. Curr Osteoporos Rep. 2007;5: Bai Y, Yang F, Xuan K, et al. Inhibition of RANK/RANKL signal transduction pathway: a promising approach for osteoporosis treatment. Med Hypotheses. In press. 13. Whitfield JF, Morley P, Willick GE. The parathyroid hormones: bone-forming agents for treatment of osteoporosis. Med Gen Med. 2000;2(4). [Formerly published in Medscape Women s Health ejournal 5(5),2000]. Available at: Accessed August 28, Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. N Engl J Med. 2007;357: Styrkarsdottir U, Halldorsson BV, Gretarasdottir S, et al. Multiple genetic loci for bone mineral density and fractures. N Engl J Med. 2008;358: Vol. 5, No. 7 October 2008