Clinical Therapeutics/Volume ], Number ], 2015

The Pathophysiology and Treatment of Osteoporosis Matthew T. Drake, MD, PhD1; Bart L. Clarke, MD1; and E. Michael Lewiecki, MD, FACP, FACE2 1

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota; and 2New Mexico Clinical Research & Osteoporosis Center, University of New Mexico School of Medicine, Albuquerque, New Mexico

ABSTRACT Purpose: The objectives of this article are to review the pathophysiology of bone loss associated with aging and to review current pharmacologic approaches for the treatment of osteoporosis. Methods: A literature search with PubMed was performed with the terms osteoporosis and pathophysiology and osteoporosis and treatment and limited to studies written in English that were published within the preceding 10 years. Given the large number of studies identified, we selectively reviewed those studies that contained primary data related to osteoporosis pathophysiology or osteoporosis pharmacologic treatments and references included within selected studies identified from abstract review. Findings: Published studies have consistently reported that osteoporosis in older adults is caused by an imbalance of bone resorption in excess of bone formation. The dominant factor leading to bone loss in older adults appears to be gonadal sex steroid deficiency, with multiple genetic and biochemical factors, such as vitamin D deficiency or hyperparathyroidism, that may accelerate bone loss. Conditions that adversely affect growth and development may limit development of peak bone mass and accelerate subsequent bone loss. Studies of bone microarchitecture have shown that trabecular bone loss begins in the third decade of life, before gonadal sex steroid deficiency develops, whereas cortical loss typically begins in the sixth decade, about the time of menopause in women and about the same age in men. Antiresorptive agents for the treatment of osteoporosis act primarily by limiting osteoclast activity, whereas osteoanabolic agents, such as teriparatide, act primarily by stimulating osteoblastic bone formation. Clinical investigation of new compounds for the treatment of osteoporosis is mainly directed to those that stimulate bone formation or differentially decrease

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bone resorption more than bone formation. Therapies for osteoporosis are associated with adverse effects, but in patients at high risk of fracture, the benefits generally far outweigh the risks. Implications: Current osteoporosis therapies mitigate or reverse the loss of bone associated with agerelated decreases of gonadal sex steroids, increase bone strength, and reduce fracture risk. With improved knowledge of the pathophysiology of osteoporosis, new targets for therapeutic intervention have been identified. Clinical investigations of potential new treatments for osteoporosis are primarily directed to stimulating osteoblastic bone formation or to modulating the balance of bone resorption and formation in ways that improve bone strength. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: aging, bisphosphonate, bone, bone mineral density, menopause, osteoporosis.

INTRODUCTION As described in the National Institutes of Health Consensus Development Conference Statement,1 osteoporosis is a skeletal disorder characterized by diminished bone strength that results in increased fracture risk, with bone strength a function of both bone mineral density (BMD) and bone quality. BMD is commonly assessed clinically by dual-energy x-ray absorptiometry (DXA), a technology that measures integrated cortical and trabecular areal (2-dimensional) BMD at several skeletal sites. Bone quality refers to the non-BMD determinants of bone strength Accepted for publication June 2, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.06.006 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics that are less easily measured, including bone microarchitecture, degree of mineralization, remodeling activity, and microdamage accumulation.1 Epidemiologic data have convincingly indicated that bone loss, as assessed with BMD testing by DXA, occurs in both women and men as part of the natural aging process.2 Associated with this bone loss is an increased fracture risk. Current estimates are that  40% of white women aged 450 years will experience an osteoporosis-related fracture, with this risk rising to nearly 50% if vertebral fractures identified by imaging, rather than clinical history, are included.3 Similarly, it is estimated that  13% of men will experience an osteoporosis-related fracture.4 Accordingly, osteoporosis and osteoporosis-related fractures are a major public health concern and impose enormous health care costs. In 2005, annual costs for osteoporosis-related fractures were US$13.7 to US$20.3 billion, an amount expected to rise to US$25.3 billion annually by 2025 due to a projected 48% increase in fractures.5 Therefore, identifying and treating persons at greatest fracture risk is of critical importance. Evidence supports the cost-effectiveness of pharmacologic intervention for the treatment of patients with prior fragility fractures, low bone mass (osteopenia) and additional clinical risk factors, or osteoporosis as defined by the World Health Organization (DXA T-score r –2.5).6 As our understanding of human bone biology has evolved over the past several decades, so too has our ability to provide increasingly targeted therapies for the treatment of osteoporosis. Central to this has been development of an ever-growing pharmacologic armamentarium of medications proven in clinical trials to reduce fracture risk by limiting ongoing bone loss and/or augmenting existing bone mass. The objectives of this article are to review the pathophysiology of bone loss associated with aging and to review current pharmacologic approaches for the treatment of osteoporosis.

METHODS A literature search through PubMed was performed with the terms osteoporosis and pathophysiology and osteoporosis and treatment and limited to studies written in English that were published within the preceding 10 years. Given the large number of studies identified, we selectively reviewed those studies that contained primary data related to osteoporosis

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pathophysiology or osteoporosis pharmacologic treatments and references included within selected studies identified from abstract review.

AGE-ASSOCIATED CHANGES IN BONE MASS AND MICROARCHITECTURE Until recently, it was believed that from the end of the pubertal growth spurt (the time point at which peak bone mass is attained) until the onset of middle age, both men and women maintained their skeletons without substantial bone loss or changes in skeletal microarchitecture. This belief was predicated on crosssectional and longitudinal skeletal measurements performed by DXA. Although it was well recognized that bone remodeling was active during this period of adulthood, it was generally thought that bone resorption was evenly matched by bone formation, resulting in stability of bone mass and maintenance of skeletal integrity. More recent work that used quantitative computed tomography (QCT), however, has found that, contrary to previous beliefs, large decreases in volumetric BMD begin as early as the third decade in both sexes, ultimately resulting in lifetime losses at the spine, a skeletal site consisting primarily of trabecular bone, of 45% in men and 55% in women.7 In women, both DXA and QCT imaging found that bone loss at the spine accelerates at the time of the menopausal transition, with loss of  20% to 30% of trabecular bone mass over the 6- to 10-year perimenopausal time period.7,8 By comparison, 5% to 10% of cortical bone is lost during the female menopausal transition. A subsequent phase of slower but continuous bone loss predominates after menopause. In this second phase, which lasts throughout the remaining life span unless pharmacologic intervention is undertaken, cortical and trabecular bone loss occur at slower, more similar rates.8 By comparison, because men do not undergo a menopausal equivalent, they do not sustain the early accelerated trabecular bone loss that occurs in women and so lose comparatively less bone than women. Although trabecular bone loss begins early in both men and women, evidence is good that relatively little cortical bone is lost in either sex until middle age. Thus, epidemiologic analysis of a cross-sectional cohort of men and women in whom QCT imaging was performed at the distal radius, a site composed primarily of cortical bone, found that from approximately

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M.T. Drake et al. age 50 years onward there is a slow nearly linear decline in volumetric BMD which persists throughout the remaining life span.7 Although this decline in women (28%) is greater than that in men (18%), this difference appears to reflect partially the greater bone loss that occurs in women during the perimenopausal and early menopausal transition. Concomitant with these declines in trabecular and cortical bone mass are important alterations in skeletal geometry that occur in both women and men as a result of the ongoing remodeling that takes place during the normal aging process. Because of the potential for important effects on skeletal strength, the remodeling-associated changes in bone crosssectional area, primarily affecting cortical bone, are of greatest interest.9 Thus, although endocortical resorption leads to decreases in cortical thickness and area, concurrent periosteal apposition of bone, albeit occurring more slowly than the concurrent endocortical resorption, leads to displacement of the cortex away from the central axis of the bone. Importantly, this net outward displacement provides a relative increase in bone strength against both axial compression and bending forces, thereby partially mitigating the deleterious biomechanical effects on bone that result from cortical thinning and increased cortical porosity.9 Despite these compensatory remodeling effects, however, the progressive bone loss and skeletal macroarchitectural and microarchitectural changes that occur predispose aging adults to substantial increases in fracture risk. Thus, in women the incidence of distal forearm fractures begins to rise markedly in the perimenopausal period before reaching a steady rate of fractures after 15 years.10 Similarly, the incidence of vertebral fractures in women begins to increase around the time of the menopause; however, rather than reaching a plateau as occurs with forearm fractures, the incidence of vertebral fractures in women continues to rise nearly linearly throughout the remainder of the life span. Finally, although female hip fracture rates initially increase in unison with rates of vertebral fractures, there is a near exponential increase in hip fracture incidence, beginning at approximately age 65 years in women. By comparison, men have few distal forearm fractures even with advanced age.10 Similar to women, however, the incidence of both vertebral and hip fractures increases markedly with aging in men,

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although the increased rates for both vertebral and hip fractures in men are delayed by 1 decade relative to women, again likely reflecting partially the absence of the male equivalent to the menopause and the associated rapid bone loss that occurs during this time in women.

HORMONAL BASIS FOR BONE LOSS WITH AGING As noted in the section above, trabecular bone loss in both men and women, as measured by QCT, begins in the third decade, a period when sex steroid concentrations (estrogen in women and testosterone in men) are typically within the normal range and thus sufficient. Reasons for trabecular bone loss at this stage of life remain unclear, but they suggest that our current understanding of skeletal changes with aging remains incomplete.

Bone Loss in Women With the menopausal onset of ovarian failure, estrogen concentrations decline rapidly. Over the menopausal transition, serum estradiol concentrations decline by 85% to 90%, whereas serum concentrations of estrone (an  4-fold weaker estrogen) decline by 65% to 75% compared with premenopausal estrogen concentrations.11 This decline is closely paralleled by a period of accelerated and progressive bone loss. Although measured rates of bone resorption and formation are approximately matched before the menopausal onset due to the coupled relation between bone-resorbing osteoclasts and bone-forming osteoblasts, the decreased estrogen concentrations associated with menopause result in increases in both bone resorption and formation, with resorption outstripping formation. Accordingly, an increase is found in the activation frequency rate of basic multicellular units composed of osteoclasts and osteoblasts that sequentially resorb old bone and form new bone. Thus, more sites on the bone surface are actively undergoing resorption, with prolongation of the osteoclast resorption time, and relative shortening of the time for osteoblastic bone formation.12,13 With these menopausal changes, biochemical markers of bone formation and resorption, measured in either blood or urine, are substantially increased. However, although bone resorption increases by 90% compared with premenopausal amounts, bone formation increases by only  45%, consistent with

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Clinical Therapeutics the net bone loss that occurs.14 Associated with this net effective increase in bone resorption is an efflux of calcium from the resorbed bone mineral into the extracellular fluid, an effect that necessitates physiologic compensation to prevent development of hypercalcemia. Compensatory mechanisms include decreased renal calcium reclamation,15 reduced intestinal calcium absorption,16 and a reduction in parathyroid hormone secretion.17 Collectively, these changes result in a net negative whole-body calcium balance with resultant skeletal demineralization. Critically, these compensatory mechanisms appear to result directly from the marked reduction in circulating estrogen concentrations, because estrogen replacement to physiologic concentrations results in preservation of renal calcium reabsorption and intestinal calcium uptake.18 Apart from these effects on calcium metabolism, a molecular understanding of the direct effects of estrogen deficiency on bone cells (osteoblasts, osteoclasts, and osteocytes) remains an area of active study.19 As previously described, osteoclast activity increases substantially at the menopausal transition associated with decreases in estrogen concentrations. As reported in both in vitro and in vivo studies, in the eugonadal state, estrogen suppresses receptor activator of nuclear factor-κ B ligand (RANKL); this is a master regulatory molecule, normally expressed on the cellular membrane of bone marrow stromal cells/osteoblast precursors and T and B cells, that promotes osteoclast differentiation, formation, and survival after binding to RANK on the cell surface of osteoclast lineage cells.20 In addition, estrogen increases the expression of osteoprotegerin (OPG), a soluble decoy receptor for RANKL, by cells of the osteoblast lineage to thereby limit osteoclast development.21 With diminished estrogen concentrations, RANKL concentrations increase and OPG concentrations decrease; together this increase in the RANKL/OPG ratio results in increased osteoclastogenesis and increased osteoclast activity. In addition to modulating both RANKL and OPG concentrations, estrogen also suppresses the expression of a variety of other cytokines produced by cells of the bone marrow microenvironment which were shown to play roles in bone resorption. These cytokines include macrophage colony-stimulating factor,22 interleukin (IL)-1 and IL-6,23 tumor necrosis factor α,24 and prostaglandins.25 Importantly, the roles of

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both IL-1 and tumor necrosis factor α were found in direct human interventional studies in which pharmacologic blockade of each cytokine in early postmenopausal women made acutely estrogen deficit was partially able to diminish the expected rise in skeletal resorption markers.26 Beyond its role in mediating osteoclastogenesis and osteoclast activity, estrogen was also shown to mediate apoptosis in both osteoclast precursors and mature osteoclasts via regulation of transcriptional activity.27,28 Estrogen also has important effects on bone formation via its effects on osteoblasts. Estrogen promotes differentiation of mesenchymal stromal cells toward the osteoblast lineage, increases differentiation of preosteoblasts to mature osteoblasts, and reduces apoptosis in both mature osteoblasts and osteocytes. Further, estrogen increases the production of growth factors, including insulin-like growth factor 1 (IGF-1) and transforming growth factor-β, and procollagen synthesis in osteoblasts. Estrogen also appears to have important suppressive effects on both circulating and bone marrow amounts of the potent osteocyteproduced Wnt-signaling pathway antagonist sclerostin,29 suggesting that estrogen-induced decreases in sclerostin amounts may be an important method by which estrogen affects both skeletal anabolism and homeostasis.30 With the menopausal decline in estrogen concentrations there is a corresponding adaptive rise in circulating concentrations of follicle-stimulating hormone (FSH) due to loss of feedback inhibition. Importantly, this rise in FSH was shown to correlate more closely in perimenopausal women with decreases in BMD at the hip and spine and with markers of bone resorption than changes in estradiol concentrations.31,32 Accordingly, this observation lead to the hypothesis that FSH may have direct effects on bone cell function, a result supported by studies in a mouse model of osteoporosis.33 To directly assess whether FSH has similar effects in humans, a direct interventional study of postmenopausal women was undertaken.34 In these women, in whom FSH concentrations were high due to their postmenopausal status but hormonal concentrations other than FSH were low and unchanging, FSH concentrations were pharmacologically suppressed via treatment with a gonadotropin-releasing hormone agonist or placebo, with all women also undergoing suppression of endogenous estrogen concentrations by

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M.T. Drake et al. aromatase inhibitor treatment. In marked contrast to the results described in mice, however, markers of bone resorption were unchanged, with no differences found between postmenopausal women in whom FSH concentrations remained elevated and women in whom FSH concentrations were suppressed. These results strongly suggest that in humans FSH does not play an important role in postmenopausal bone loss. Finally, although it was suggested that testosterone (perhaps via aromatization to estrogen) in women may be important for increasing bone formation and likely periosteal bone apposition during skeletal growth, little evidence suggests that the low circulating testosterone concentrations in postmenopausal women have any relevant impact on bone loss after the menopausal onset.2

Bone Loss in Men Although osteoporosis is a disease that mostly affects aging women, it is also a major threat to the health of aging men, in whom it is associated with substantial morbidity, mortality, and health care costs.35 As with bone loss in women, bone loss in men can be broadly categorized as age associated, because of other secondary causes, or resulting from a combination of these effects. Compared with postmenopausal women, aged men lose approximately one-half as much bone and have approximately one-third as many fractures.17 As in women, trabecular bone loss begins in the third decade shortly after maximum bone mass has accrued, at a time when sex steroid (primarily testosterone) concentrations are within the normal or sufficient range.7 Unlike women, who undergo a natural, age-associated, abrupt decline in sex steroid concentrations at the time of the menopause, men do not experience a menopausal equivalent. Rather, men undergo a 42-fold increase in sex hormone-binding globulin concentrations over the life span. Because of this increase in sex hormone-binding globulin concentration, amounts of bioavailable (composed of free and albumin-associated) testosterone decline by approximately two-thirds over the course of the male life span.36 Further, because testosterone can undergo aromatization to estrogen, values of bioavailable estrogen concentrations also decrease by 50% with aging. Although testosterone is the primary sex steroid in men, solid evidence is now available from

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cross-sectional37–40 and longitudinal41 studies that BMD in men correlates more closely with circulating bioavailable estradiol concentrations than with testosterone concentrations. Intriguingly, in older men it appears that there may be a minimum threshold of 15 pg/mL, below which male bone loss (both cortical and trabecular) occurs.42 Although the epidemiologic data in the above paragraphs are suggestive of a central role for estradiol in maintenance of male skeletal health with aging, the described findings are by definition correlative rather than direct evidence of a role for estrogen in male skeletal health. To directly assess the relative effects of both estrogen and testosterone on skeletal metabolism in men, Falahati-Nini et al43 undertook a direct intervention study in which elderly men were pharmacologically made estrogen deficient, testosterone deficient, or deficient in both sex steroids, and biochemical measurement of bone resorption and formation markers were determined. Consistent with the epidemiologic data in the above paragraphs, estrogen replacement alone was able to nearly completely prevent increases in serum markers of bone resorption, whereas testosterone alone was substantially less effective at mitigating this rise. In comparison, bone formation marker assessment revealed that estrogen was able to prevent the decrease in bone formation marker N-terminal extension peptide of type I collagen that occurred when men were deficient for both sex steroids. Collectively, these data are supportive of a dominant role of estrogen for reducing the risk of bone loss with aging in men. Finally, although serum estradiol concentrations may be most relevant for predicting bone loss in men with aging, evidence again suggests that testosterone is likely important for increasing periosteal cortical bone apposition, although the evidence most supportive of this to date is from animal models that may not always accurately reflect human biology.44

Nonsex Steroid Hormonal Changes with Aging Although available evidence supports a role for changes in sex steroids as the predominant hormonal factor underlying bone loss with aging, it is important to recognize that nonsex steroid hormonal changes also occur in both sexes. Perhaps of greatest significance to bone biology are the decreases in both the frequency and amplitude of growth hormone secretion

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Clinical Therapeutics by the pituitary gland,45 changes that directly lead to diminished hepatic production of IGF-1 and IGF-2, hormones with well-recognized roles in mediating osteoblast differentiation and activity.46,47 Contemporaneous with these noted decreases in IGF concentrations are increased concentrations of the IGF inhibitory binding protein, IGFBP-2, concentrations of which were also shown to negatively correlate with BMD in aged adults.48 Finally, it is likely that intrinsic changes within cells of the osteoblast and perhaps osteoclast lineage also occur with aging. Such changes may be independent of sex steroid or other hormonal changes, however, and may relate to increased cellular senescence that is a recognized hallmark of aging bone.49

FACTORS BEYOND AGE-ASSOCIATED BONE LOSS In addition to normal age-related bone loss, numerous secondary causes of bone loss and/or increased fracture risk also exist. Such risk factors can be placed into broad categories, including medications such as glucocorticoids, antiestrogens, and antiepileptics; endocrine disorders such as hyperparathyroidism, hyperthyroidism, hypogonadism, diabetes mellitus, and vitamin D deficiency; rheumatologic conditions, including systemic lupus erythematosus and rheumatoid arthritis; neurologic conditions such as spinal cord injury or Parkinson disease; hematologic diseases, including monoclonal gammopathy of undetermined significance, multiple myeloma, and systemic mastocytosis; malabsorptive conditions such as celiac and inflammatory bowel disease and bariatric surgery; transplantation; and a variety of other conditions. Collectively, these conditions can induce increased skeletal fragility for a variety of reasons. Although too numerous to enumerate herein, potential causes include impairment of maximum bone mass accrual (eg, in patients with malnourishment during their years of peak bone mass acquisition), impaired bone quality (eg, in patients with poorly controlled diabetes mellitus50), either relative or partial skeletal unloading (eg, with decreased ambulation or spinal cord injury) that leads to bone loss, iatrogenic (eg, prolonged supraphysiologic corticosteroid dosing for the treatment of rheumatologic conditions), among others. For a more comprehensive review of the pathophysiology of and management approach to many common

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secondary causes of osteoporosis, refer to an excellent recent publication focused on this topic.51

TREATMENT OF OSTEOPOROSIS Although treatment is most frequently associated with a pharmacologic approach, it is important to recognize that for the optimal treatment of osteoporosis, nonpharmacologic approaches are also important to limit fracture risk.52 Nonpharmacologic interventions include limiting the risk of falls; using proper techniques when lifting; maintaining adequate intake of calcium, vitamin D, and protein; performing adequate weight-bearing physical activity and exercise to maintain or improve balance and posture; and making appropriate lifestyle changes, such as smoking cessation and moderating alcohol intake. These therapeutic adjuncts should be addressed with patients in addition to pharmacologic intervention.

Estrogen/Selective Estrogen Receptor Modulators Treatment of postmenopausal women with pharmacologic doses of estrogen was shown to have antiresorptive effects on the skeleton and to prevent bone loss. Bone histomorphometry has found that estrogen may also have local anabolic effects. In a longitudinal study in which iliac crest bone biopsies were performed to monitor response to therapy, pharmacologic estrogen treatment for 6 years resulted in increases of 61% in trabecular bone volume and 22% in trabecular wall thickness.53 Despite this direct evidence of a beneficial role for estrogen in the treatment of postmenopausal osteoporosis and epidemiologic evidence from longitudinal imaging and fracture studies54–56 that found efficacy, the use of estrogen for the treatment and prevention of osteoporosis has waned considerably because of concerns related to the potential for nonskeletal adverse effects, as seen in the Women’s Health Initiative study,57 and the availability of other agents with different safety profiles. Raloxifene is a selective estrogen receptor modulator (SERM) that is approved for treatment and prevention of postmenopausal osteoporosis. Most clinicians use raloxifene for the management of osteoporosis in patients with contraindications to other antiresorptive agents or for the treatment of women desirous of breast cancer prevention in whom enhanced skeletal health would be an additional

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M.T. Drake et al. benefit.58 Of note, the third-generation SERM bazedoxifene in combination with conjugated estrogens59 was recently approved by the US Food and Drug Administration (FDA) for the prevention of postmenopausal osteoporosis.

Bisphosphonates Unlike estrogen/SERMs that function as hormones/ hormone analogues by binding to cellular receptors to exert their functions, bisphosphonates are chemically stable inorganic pyrophosphate analogues with extremely high affinity for hydroxyapatite, the mineral component of bone.60 It is this property that allows bisphosphonates to achieve high local concentrations within the skeleton. Because of this extreme tropism for bone, bisphosphonates exert important pharmacologic effects on skeletal disorders with enhanced or imbalanced bone remodeling, as frequently occurs with bone loss.61 Although no longer commonly used, first-generation non–nitrogen-containing bisphosphonates (clodronate, etidronate, and tiludronate) function by becoming incorporated into nonhydrolyzable adenosine triphosphate (ATP) analogues.60 After osteoclastmediated endocytosis from the bone surface, these bisphosphonate-containing ATP analogues become cytotoxic, likely because of the inhibition of various ATP-dependent cellular processes, resulting in osteoclast apoptosis. All second- and third-generation bisphosphonates (alendronate, risedronate, ibandronate, and zoledronate) have nitrogen-containing side chains. Because of structural differences with first-generation bisphosphonates, these second-generation bisphosphonates adhere even more tightly to hydroxyapatite mineral in bone. In addition, after osteoclast endocytosis, they induce osteoclast apoptosis via a mechanism distinct from that of first-generation bisphosphonates, namely via inhibition of farnesyl pyrophosphate synthase (FPPS).62,63 As a result of FPPS inhibition, the posttranslational lipid modification of small guanosine triphosphate-binding proteins within osteoclasts is inhibited, again ultimately leading to osteoclast apoptosis. This inhibition of osteoclast function is most frequently monitored clinically via longitudinal assessment of changes in BMD, or more proximally via evidence of a reduction in serum or urine biochemical markers of bone resorption. Bisphosphonate skeletal uptake depends on delivery method. Oral

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bisphosphonates are minimally absorbed by the intestine, with o1% bioavailability due to their hydrophilicity, whereas intravenous preparations are 100% bioavailable. Bisphosphonates have variable potency for hydroxyapatite mineral binding and consequent variable binding-site availability, effect on bone turnover, and FPPS inhibition efficacy.61 Biologic half-lives of nitrogen-containing bisphosphonates remain a topic of debate, with data suggesting that those with the greatest potency for bone mineral may reside in the skeleton for Z5 years after administration.64

Alendronate

Alendronate became the first nitrogen-containing bisphosphonate to receive FDA approval in the United States. As shown in the Fracture Intervention Trial (FIT) in which 2027 postmenopausal women aged 55 to 81 years with low femoral neck BMD were randomized to receive either placebo or daily oral alendronate, treatment with alendronate decreased new vertebral morphometric (ie, identifiable radiographically but not necessarily clinically) fractures by 47% and hip fractures by 51% compared with placebo.65 In the subsequent FIT Long-term Extension (FIT-FLEX) study of this same trial cohort, women who had received alendronate treatment for 5 years were subsequently randomized to receive further alendronate treatment for 5 additional years (for a total of 10 years of alendronate treatment) or placebo.66 In comparison with women who continued alendronate treatment, women in the placebo group had small but statistically significant declines in BMD and a slightly increased risk of clinical (but not morphopmetric) vertebral fractures; however, no differences were seen for either nonvertebral or all clinical fractures. In post hoc analyses of FIT-FLEX data, continuing alendronate for 10 years instead of stopping after 5 years reduced nonvertebral fracture risk in women without prevalent vertebral fracture whose femoral neck T-scores after 5 years of alendronate were r–2.5 but did not reduce the risk of nonvertebral fractures when the T-score was 4–2.0.67

Risedronate As with alendronate, the oral bisphosphonate risedronate was shown in large, randomized placebo-controlled trials to increase BMD and to decrease fracture risk. In the Vertebral Efficacy with Risedronate Therapy study of 2458 postmenopausal

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Clinical Therapeutics women from North America aged o85 years and with Z1 vertebral fracture at study entry, treatment with daily risedronate for 3 years reduced the incidence of new vertebral fractures by 41% and nonvertebral fractures by 39%.68 Similar findings were reported from a parallel trial conducted in Europe and Australia.69

Ibandronate Ibandronate was the third nitrogen-containing oral bisphosphonate to receive approval in the United States. Unlike alendronate and risedronate, both oral and intravenous formulations of ibandronate are available. In addition, although alendronate and risedronate have proven efficacy for the prevention of vertebral, nonvertebral, and hip fractures, ibandronate was shown in trials to only reduce the risk of vertebral fractures,70 although issues related to determination of the most effective dose and other trial design concerns may be partly to blame rather than inherent reduced pharmacologic efficacy per se.71

Zoledronate Zoledronate is the most frequently used intravenous bisphosphonate in the United States for the treatment of osteoporosis. When administered once yearly for 3 years in the Health Outcomes And Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) trial, which included nearly 3900 postmenopausal women with a mean age of 73 years in each arm, zoledronate decreased the risk of vertebral fractures by 70%, hip fractures by 41%, and nonvertebral fractures by 25%72 compared with placebo.

Potential Limitations Associated with Bisphosphonate Therapy Collectively, all second- and third-generation bisphosphonates are powerful antiresorptive agents that effectively limit osteoclast-mediated bone resorption, leading to increases in BMD and decreases in fracture rates. Despite these skeletal benefits, however, potential adverse events associated with their use may occur and limit their use in some patients. Reported shortterm risks include upper gastrointestinal intolerance with dyspepsia, nausea, or abdominal pain with oral bisphosphonates; acute-phase reactions that consist of myalgias, arthralgias, and fever after intravenous bisphosphonate infusion; severe chronic musculoskeletal pain; hypocalcemia, which may occur primarily after

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intravenous bisphosphonate infusion; and ocular inflammation that necessitates ophthalmologic referral.73 More recently, rare potential adverse effects associated with prolonged bisphosphonate use for the treatment of osteoporosis were described. The incidence of osteonecrosis of the jaw (ONJ) in patients treated with bisphosphonates for osteoporosis is extremely rare, with current estimates of  1 per 10,000 to 1 per 100,000 person-years, a rate that is only slightly higher than that seen in the general population (o1 per 100,000 person-years), as described in a recent systematic review that also provided recommendations for the optimal diagnosis and management of this potential complication.74 Atypical femur fractures (AFFs), defined as substantially transverse low-trauma fractures in the subtrochanteric region or femoral diaphysis that are noncomminuted or minimally comminuted and associated with cortical thickening, are rare events in patients treated with long-term bisphosphonates for osteoporosis that may be a greater clinical concern than ONJ. As detailed in a recent task force report, the absolute risk of AFFs in patients treated with bisphosphonates for osteoporosis ranges from 3.2 to 50 per 100,000 person-years, with this risk perhaps rising in patients treated for prolonged periods to 100 per 100,000 person-years.75 Perturbations of lower limb bone geometry and Asian ethnicity may contribute to the risk of AFFs. Fractures with features similar to AFFs were reported in patients with hypophosphatasia, pycnodysostosis, and osteopetrosis. Recommendations for the recognition and medical management of patients suspected of having an incomplete (ie, involving the lateral cortex only) or complete (ie, extending through both cortices) AFF were provided in the task force report. Given that the risk of ONJ and AFF appears to rise with increased duration of therapy, the concept of a bisphosphonate drug holiday was raised, whereby withholding drug administration after at least 3 to 5 years of treatment may be followed by persistence of antiresorptive effect for a period of time while reducing the risk of ONJ and AFF. To date data are limited, primarily from the FIT-FLEX and HORIZON extension studies, to guide such considerations.76

Denosumab Denosumab is an antiresorptive agent that limits osteoclast-mediated bone resorption. Although

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M.T. Drake et al. bisphosphonates are small molecules, denosumab is a fully human monoclonal antibody that specifically binds RANKL, the master regulatory molecule required for osteoclast formation and activity, thereby preventing RANKL association with its cognate receptor RANK on the preosteoclast membrane and disrupting osteoclastogenesis. Denosumab is FDA approved for the treatment of osteoporosis and to prevent bone loss in men who receive androgendeprivation therapy for nonmetastatic prostate cancer and women who receive adjuvant aromatase inhibitor therapy for breast cancer who are at high fracture risk. As observed in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial of 7868 women aged 60 to 90 years with a T-score between –2.5 and –4.0 at the lumbar spine or total hip, denosumab delivered subcutaneously every 6 months for 3 years reduced new radiographic vertebral fractures by 68%, hip fractures by 40%, and nonvertebral fractures by 20% compared with placebo.77 In the subsequent FREEDOM extension study, treatment for an additional 3 years led to further increases in BMD at the lumbar spine, whereas the incidence of adverse events, including ONJ and AFF, remained low, albeit slightly higher than reported for long-term bisphosphonate treatment.78 In the long-term denosumab group (receiving 6 years of continuous denosumab) 4 oral events were adjudicated as consistent with ONJ during the first 3 years of the extension. Two of these patients discontinued denosumab treatment while the 2 others continued denosumab, with all 4 lesions healing with appropriate treatment. There was 1 midshaft and 1 subtrochanteric femoral fracture in the long-term group during the first 3 years of the extension, with neither of these determined to be an AFF after adjudication.

Teriparatide To date, teriparatide (recombinant human parathyroid hormone, consisting of the amino-terminal 34 amino acids of the 84 amino acid native parathyroid hormone molecule) is the only FDA-approved skeletal anabolic agent. When injected subcutaneously once daily, teriparatide increases both bone formation and resorption, with formation outweighing resorption particularly in the initial 6 to 12 months of therapy, leading to increases in bone mass. The FDA has limited teriparatide treatment to 24 months lifetime.

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Because of the potential for osteosarcoma formation that depended on the dose and duration of treatment in a preclinical rat model, the FDA mandated a postmarketing analysis study that has not shown a causal relation between teriparatide treatment and osteosarcoma development in humans after 7 years of surveillance.79 As found in the Fracture Prevention Trial, in which 1637 postmenopausal women with a prior vertebral fracture were randomized to receive treatment with teriparatide or placebo for a median of 21 months, teriparatide treatment at the FDAapproved dose of 20 μg/d reduced new vertebral fractures by 65% and new nonvertebral fractures by 53%.80 Subsequent studies have examined treatment approaches in which teriparatide is given in combination with other agents, including estrogen,81 alendronate,82 zoledronate,83 and denosumab,84 with the most substantial increases in BMD found to occur when denosumab or zoledronate was provided in combination with teriparatide.83,85 However, given the financial expense associated with teriparatide relative to other available pharmacologic agents, it is unclear how readily these provocative findings will translate to clinical practice.

Osteoporosis Treatment in Men Although most large randomized controlled trials have included only women, current clinical practice guidelines suggest that, with the exception of estrogen and SERMs, pharmacologic agents used for the treatment of bone loss in women (bisphosphonates, denosumab, and teriparatide) can be safely provided to men with osteoporosis.86 Notably, all have received FDA approval for use in men with the sole exception of ibandronate.

New Agents for the Treatment of Osteoporosis Finally, despite the availability of multiple medication classes for the treatment of osteoporosis, our evolving understanding of human bone biology has allowed for the continued development of new approaches to osteoporosis treatment. Of the agents currently in clinical trials, perhaps those with the greatest potential for changing clinical practice are inhibitors of cathepsin K and sclerostin. Cathepsin K, a cysteine protease expressed by osteoclasts, mediates bone resorption through its effects on collagen matrix degradation.87 In a Phase II clinical trial, the cathepsin K inhibitor odanacatib

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Clinical Therapeutics increased BMD at the hip and spine, and the study intriguingly found relative dissociation between measured biochemical markers of bone resorption and formation, with resorption markers decreasing to a greater extent than formation markers.88 Sclerostin, an osteocyte-secreted Wnt signaling antagonist, suppresses bone formation via its effects on osteoblast differentiation, activity, and survival. In a recent Phase II clinical trial of a humanized monoclonal antibody against sclerostin, substantial increases in bone mass at the spine and hips were observed.89 Perhaps most surprising was the observation that sclerostin antibody treatment appeared to simultaneously stimulate bone formation while suppressing bone resorption, which, if confirmed, would be a unique property among medications used for the treatment of osteoporosis. Phase III clinical trials for both agents are currently ongoing. Whether either agent will receive FDA approval is unknown, but if approved, both would be welcome additions to our current pharmacologic armamentarium for use in the treatment of osteoporosis.

CONCLUSIONS Major advances have been made in understanding the pathophysiology of osteoporosis, with ongoing research devoted to more fully understanding the genetic and molecular causes of osteoporosis. It is increasingly clear that the pathophysiology is complex and that causes of bone loss depend on the complex interplay of numerous genetic, hormonal, and molecular factors. The search for new targets for therapy continues, because all currently available agents were developed on the basis of the understanding of specific aspects of the pathophysiology. Eventual development of individualized therapy for osteoporosis will depend on recognition of the key genes and signaling pathways responsible for bone loss in a particular patient and application of therapies most likely to modulate the effects of these genes and pathways. Until individualized therapy is available, selection of osteoporosis treatment will continue to depend on assessment of patient-specific risk factors for bone loss and fracture, contraindications to therapy, patient preference, and cost.

ACKNOWLEDGMENTS All authors contributed to the literature search, writing, and revision of this manuscript.

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CONFLICTS OF INTEREST Dr Lewiecki has received institutional grant/research support from Amgen, Merck, and Eli Lilly; he has served on scientific advisory boards for Amgen, Merck, Eli Lilly, Radius Health, AgNovos Healthcare, Alexion, NPS, and AbbVie. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

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Address correspondence to: E. Michael Lewiecki, MD, New Mexico Clinical Research & Osteoporosis Center, University of New Mexico School of Medicine, 300 Oak Street NE, Albuquerque, NM 87106. E-mail: [email protected]

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