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PRINTER-FRIENDLY VERSION AT RHEUMATOLOGYPRACTICENEWS.COM
June 2013
Rheumatology Practice News SPECIAL EDITION All rights r
Stanford University School of Medicine Copyright 2013 McMahon Publishing Gr
Dr. Marcus is a retiree of Eli Lilly & Company and serves as an advisor to both Amgen Inc. and Lilly. eserved. Repr
Not long ago, FDA-approved pharmacologic oduction in whole or in part without permission is pr
options for treating patients with osteoporosis included an assortment of estrogen preparations and calcitonins. Beginning in the mid-1990s, the introduction of a potent aminobisphosphonate, alendronate (Fosamax, Merck), and a selective oup unless otherwise noted.
estradiol receptor modifier (SERM), raloxifene (Evista, Eli Lilly), began a decade-long era of dominance over the osteoporosis market by these 2 agents.
The past decade has witnessed field, with consideration of important ber of approved drugs for the has accumulated. Finally, I will not dis- excavated by resorbing cells, called remodeling event is slightly ineffi- treatment of osteoporosis, giving cuss the hygienic measures, supple- osteoclasts, which arise in the bone ohibited.
concerns regarding drugs currently the concomitant adequate intake of osteoclastic resorption is initiated, fol- ment of osteoporosis in the United tion under which the clinical trials that established efficacy of all approved stroma called preosteoblasts migrate into the resorption cavity, acquire that any increase in the overall rate process of breakdown and renewal Physiology: Bone Remodeling
ing osteoblasts, and begin to replace eton. The literature on osteoporosis iarity with remodeling to understand therapeutics is now enormous, and the mechanisms of action of osteopo- between 6 and 8 weeks, and the subsequent bone formation response, resulting hole, or lacuna, achieves antiresorptive therapy, regardless of Hence, where possible I will refer tion—the antiresorptive drugs—and a depth of about 60 microns. The which agent is considered, ultimately the reader to pivotal studies of indi- However, even in normal adults, siderable understanding about the June 2013
Rheumatology Practice News SPECIAL EDITION Table. FDA-Approved Agents for Osteoporosis Prevention and/or Treatment
clasts. Osteoclast precursor cells in the bone marrow contain the RANK factor-κB) gene. RANK is ubiquitous in multiple cells in the macrophage osteoclast response to a stimulatory protein produced by osteoblasts All rights r
Prevention and treatment; administered annually by Copyright 2013 McMahon Publishing Gr
eserved. Repr
Prevention and treatment; administered every 6 mo the dynamics of osteoclast produc-tion. OPG is considered a “decoy” OPG restricts access to RANK, and oduction in whole or in part without permission is pr
thereby puts a brake on osteoclast development. The great majority of Treatment of patients with osteoporosis and GIOP Teriparatide (hPTH[1-34]) (Forteo, Eli Lilly) at high risk for fracture; administered as once-daily agent, teriparatide (Forteo, Eli Lilly) is approved in the United States, GIOP, glucocorticoid-induced osteoporosis; SERMs, selective estrogen receptor modulators
although others are undergoing clin-ical trials.
oup unless otherwise noted.
Agents Approved for the
Evidence from the Women’s Health clinical trials over the past 15 years, later, the optimal time for using ralox- Prevention and Treatment of
Osteoporosis
on nonvertebral fracture,2,3 but in that agency policy, osteoporosis drugs ease4 and breast cancer5 tempered able toxicity in other organ systems, therapy. For women with an intact 60 mg daily, raloxifene is consid- istration of a progestin to prevent tive agent. Treatment leads rapidly hyperplasia. Some women respond endometrial hyperplasia. In the WHI, tant contributor to the mentioned (BMD) of the lumbar spine, although Various estrogen preparations side effects. Following release of the ohibited.
osteoporosis in postmenopausal gen use in the United States quickly plummeted and has not recovered. ture, but generally has not shown it does offer skeletal protection to dominant form used in the United Estrogen remains the most effective approach for managing hot flashes, sites.6 Large randomized clinical tri- and current recommendations state als with nonvertebral fracture as an trial hyperplasia and is associated erally based on anecdotal reports as short a time as is required. Such porosis do indicate a beneficial effect among women in the most severe Bisphosphonates sively more common even shortly pound, pyrophosphate, but have a SERMs have undergone late-phase consideration until at least 2 decades June 2013
Rheumatology Practice News SPECIAL EDITION details of their molecular structure. some of these differences reflect only All rights r
less of structure, bisphosphonates ing remains low as long as the drugs share certain characteristics. They are Copyright 2013 McMahon Publishing Gr
tine (<2%), therefore patients must bisphosphonates lead within a few take special precautions when using eserved. Repr
an oral form of the medications. bone formation and are thus entirely able) when the drug is consumed, used as a surrogate marker for drug and remaining upright for 30 minutes oduction in whole or in part without permission is pr
Figure 1. The drawing represents a region of
trabecular bone.
the initiation of therapy refill but are All remodeling events occur on the bone surface. (a) 90% of bone surface is generally covered by a thin layer of dormant lining cells. (b) Coalescence of osteoclast precursors at a site on the bone surface with creation of mul- tinucleated osteoclasts. (c) Osteoclasts remove a divot of bone, reach- All approved bisphosphonates rate, each trabecula has a longer ing 60 microns in depth by 6 to 8 weeks. (d) Soluble factors released by achieve a substantial reduction in period to acquire mineral until a sub- osteoclastic resorption recruit a new wave of cell proliferation (preosteo- vertebral compression fractures, sequent remodeling event affects it. blasts) into the base of the resorption cavity. (e) Preosteoblasts acquire oup unless otherwise noted.
the osteoblast phenotype. (f) Osteoblasts secrete new bone matrix, which begins to acquire mineral after a thickness of approximately 20 microns is reduce nonvertebral fractures as eral per unit of bone matrix increases achieved. (g) New mineralized bone almost fully replaces resorbed bone by approximately 6 months. Small deficits are left, reflecting remodeling inefficiency and accounting for the process of age-related bone loss. Similarly, in a large clinical trial, rise- with osteoporosis, but a subset of fracture efficacy, and with raloxifene crystallized over the appearance of nature of atypical fractures for those older frail patients who had only this estimate is only about 11%. Other The most dramatic effects of tion in the prevalence of osteoclast tures are unusual, but appear to be incidenc ohibited. e of fracture has persistently
observed with the parenteral agent bone, as these constitute regions of fragility and increased fracture risk.
1,000 participants who already had nates incorporate tenaciously into distance between the upper end of constitute a small proportion of the experienced a hip fracture, this agent bone and remain there for years. the femur and the knee. Hence, they bisphosphonates rose with reports ical stress fractures. Atypical fractures that some patients appeared with frequently are bilateral, the contralat- complication was rare and, for the on the opposite femur. The fracture not required additional label changes.
fracture site, localized periosteal reac- Considerable pharmaceutical tine dental care if they were taking tion, or “beaking,” of the lateral cortex industry effort has been made to bisphosphonates.
More recently, concern has both cortices.11 Despite the serious in 2- and 3-year clinical trials, the June 2013
Rheumatology Practice News SPECIAL EDITION Denosumab (Prolia, Amgen) is calcitonin, which as a nasal spray is a human monoclonal antibody to indicated for the treatment of post-RANKL that blocks its binding to menopausal osteoporosis. At the RANK and thereby inhibits the pro- duction and actions of osteoclasts, nasal spray calcitonin inhibits osteo-leading to a substantial reduction in at the approved dose of 60 mg. a decrease in vertebral, but not non-The pivotal 36-month clinical trial vertebral fracture; however, this trial All rights r
Copyright 2013 McMahon Publishing Gr
hip fracture.16 Denosumab was well that it is associated with an overall eserved. Repr
tolerated, and showed no increase increased risk for malignancies, and in serious infections or malignancy. Figure 2. Osteoclasts in resorption lacunae.
Reproduced from Lee C, Einhorn T: In Marcus R, Feldman D, Kelsey J RANK is an active participant in the (Eds.). Osteoporosis, 2nd Edition, Academic Press 2001, with permission action likely will result in limitation or oduction in whole or in part without permission is pr
A key feature of denosumab is the United States, but as of this writ- that, unlike bisphosphonates, the ing the FDA has not rendered a final little additional therapeutic effect drug does not accumulate in the skel- and even less-frequent regimens. concept, but a reasonable approach to make significant inroads on the First, it can be argued that some ceptible to ONJ and atypical frac- patients who originally had mild tures, but that has not been the end” of the molecule oup unless otherwise noted.
Alendronate was the first oral deficits in BMD (ie, BMD T scores case; the occurrence of both events porosis market, and consequently qualify for the designation of osteo- tion it still occupies. In recent years, scribed bisphosphonates to begin with denosumab has not been exten- alendronate has been available as with. In such cases, termination of sive, and the causality of this drug for a generic oral product. Although therapy after 4 to 5 years is appro- generic drugs must show identical priate. In others, a good therapeutic a lower risk for fracture, and it should gle-chain polypeptide hormones sequence and understand the struc- ohibited.
over time. However, some patients the primary secretory product of the lished that generic alendronate despite a substantial improvement cies, and in humans they are pro- duced and secreted by the C cells species. Trials of this peptide con- ing gastrointestinal symptoms, and tion, it seems inappropriate to termi- appear primarily to be involved in osteoporosis throughout the 1980s calcium homeostasis, inhibiting the and 1990s demonstrated substan- non-bisphosphonate) of drug may actions of mature osteoclasts and tial increases in BMD at the spine showing phosphaturic effects on and proximal femur. The pivotal trial the renal tubule. Demonstrating an of recombinantly produced TPTD term bisphosphonate use, many and atypical fractures have been as even individuals who have under- gone total thyroidectomy—and incidence of moderate and severe patients stop therapy after 4 to 5 resorptive therapy, although it is therefore produce no calcitonin— still too early to know the extent have normal skeletal physiology.
ies widely among animal species; tered daily subcutaneous injection at June 2013
Rheumatology Practice News SPECIAL EDITION antifracture efficacy is essential. In the men and postmenopausal women apy, the important feature is simply to therapy. Eur Radiol. 2012;23(1):222-227.
induced osteoporosis. The duration sorptive agent should be useful.
Several studies have addressed future therapies in medical practice months. This limit reflects the fact that Mineral Research. J Bone Miner Res. treatment efficacy and safety have therapy with TPTD and an antire- not been established beyond that sorptive drug might offer additive or References
femoral fractures: report of a task force All rights r
ies have not achieved encouraging 1. Lindsay R, Hart DM, Forrest C, Baird Mineral Research. J Bone Miner Res. in oöphorectomized women. Lancet. Copyright 2013 McMahon Publishing Gr
Effects of estrogen plus progestin on risk of fracture and bone mineral density: the eserved. Repr
certainty, although it is reassuring that Women’s Health Initiative randomized trial. JAMA. 2003;290(13):1729-1738.
regimen that has been shown to 3. Jackson RD, Wactawski-Wende J, 1-year results of a retrospective patient LaCroix AZ, et al. Effects of conjugated coma safety signal has been detected.
chart review analysis. Rheumatol Int. equine estrogen on risk of fractures and The anabolic action of TPTD is fracture is monotherapy with TPTD BMD in postmenopausal women with hysterectomy: results from the Women’s largely achieved through activation at a daily dose of 20 mcg.
15. Lai PS, Chua SS, Chong Y, Chan SP. The Health Initiative randomized trial. J Bone oduction in whole or in part without permission is pr
effect of mandatory generic substitution Miner Res. 2006;21(6):817-828.
patients’ adherence. Curr Med Res Opin. et al. Postmenopausal hormone therapy and risk of cardiovascular disease by blasts without an initial resorption other antiresorptive agents may age and years since menopause. JAMA. eling is not perfectly efficient, an than 400 postmenopausal women 5. Chlebowski RT, Hendrix SL, Langer RD, et al. Infl uence of estrogen plus progestin Trial. JAMA. 2003;289(24):3243-3253.
17. Chesnut CH III, Silverman S, Andriano K, et oup unless otherwise noted.
al. A randomized trial of nasal spray salmon 3-year randomized clinical trial. JAMA. study. PROOF Study Group. Am J Med. 7. Delmas PD, Genant HK, Crans GG, et al. Severity of prevalent vertebral fractures 18. Neer RM, Arnaud CD, Zanchetta JR, et and the risk of subsequent vertebral and al. Effect of parathyroid hormone (1-34) nonvertebral fractures: results from the MORE trial. Bone. 2003;33(4):522-532.
on fractures and bone mineral density in 8. Black D, Cummings SR, Karpf DB, et al. the United States was not successful.
Alendronate reduces the risk of fractures N Engl J Med. 2001;344(19):1434-1441.
in women with existing vertebral fractures: After a course of TPTD therapy Conclusion
results of the Fracture Intervention Trial. Lancet. 1996;348(9041):1535-1541.
interpretation of rat carcinogenicity studies 9. McClung MR, Geusens P, Miller PD, et al. for PTH (1–34) and human PTH (1–84).
Effect of risedronate on the risk of hip J Bone Miner Res. 2008;23(6):803-811.
tive drug to maintain the benefits both the antiresorptive and anabolic fracture in elderly women. N Engl J Med. ohibited.
20. Cosman F, Eriksen EF, Recknor C, et al. that have been achieved. With this categories. Inhibitors of the enzyme Effects of intravenous zoledronic acid plus approach, treatment goals for the cathepsin-K, an important part of 10. Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures in postmenopausal osteoporosis. J Bone and mortality after hip fracture. N Engl J from those applicable to first-line submitted for FDA approval within Miner Res. 2011;26(3):503-511.

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