The n e w e ng l a n d j o u r na l of m e dic i n e
From the Division of Rheumatology and Clinical Immunology, 9. Clegg DO, Reda DJ, Harris C, et al. Glucosamine, chondroi-
University of Maryland School of Medicine, Baltimore.
1. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the
prevalence of arthritis and selected musculoskeletal disorders in
the United States. Arthritis Rheum 1998;41:778-99.
2. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for
the medical management of osteoarthritis. II. Osteoarthritis of
the knee. Arthritis Rheum 1995;38:1541-6.
3. American College of Rheumatology Subcommittee on Osteo-
arthritis Guidelines. Recommendations for the medical manage-
ment of osteoarthritis of the hip and knee: 2000 update. Arthri-
tis Rheum 2000;43:1905-15.
4. Pendleton A, Arden N, Dougados M, et al. EULAR recommen-
dations for the management of knee osteoarthritis: report of a
task force of the Standing Committee for International Clinical
Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis
2000;59:936-44.
5. Jordan KM, Arden NK, Doherty M, et al. EULAR recommen-
dations 2003: an evidence based approach to the management of
knee osteoarthritis: report of a task force of the Standing Com-
mittee for International Clinical Studies Including Therapeutic
Trials (ESCISIT). Ann Rheum Dis 2003;62:1145-55.
6. Hochberg MC. Multidisciplinary integrative approach to
treating knee pain in patients with osteoarthritis. Ann Intern
Med 2003;139:781-3.
7. Berman BM, Bausell RB, Lee WL. Use and referral patterns
for 22 complementary and alternative medical therapies by mem-
bers of the American College of Rheumatology: results of a na-
tional survey. Arch Intern Med 2002;162:766-70.
8. Committee on the Use of Complementary and Alternative
Medicine by the American Public, Institute of Medicine. Com-
plementary and alternative medicine in the United States. Wash-
ington, D.C.: National Academies Press, 2005.
The Long and the Short of Bone Therapy
Michael P. Whyte, M.D.
In 2004, the Surgeon Generals report on bone
health highlighted osteoporosis as an important
and growing national medical problem.1 The au-
thors of this report recognized that identifica-
tion and treatment of this condition in women
and men alike has lagged behind the increasing
availability of instruments with which to detect
low bone mass and the advancing pharmaco-
logic approaches for prevention and therapy.
Lack of compliance with approved drug regi-
mens can hinder progress in the treatment of
osteoporosis.2 In this issue of the Journal, from a
study that was sponsored, designed, and analyzed
by Amgen, McClung et al.3 report on the safety and
efficacy of various doses of denosumab (former-
ly known as AMG 162), a humanized monoclonal
antibody to the receptor activator of nuclear
factor-B (RANK) ligand (RANKL). The antibody
was administered subcutaneously either every
three months or every six months for one year
860 n engl j med 354;8 www.nejm.org
The New England Journal of Medicine
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Copyright 2006 Massachusetts Medical Society. All rights reserved.
tin sulfate, and the two in combination for painful knee osteo-
arthritis. N Engl J Med 2006;354:795-808.
10. Berman BM, Lao L, Langenberg P, Lee WL, Gilpin AMK,
Hochberg MC. Effectiveness of acupuncture as adjunctive thera-
py in osteoarthritis of the knee: a randomized, controlled trial.
Ann Intern Med 2004;141:901-10.
11. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucos-
amine and chondroitin for treatment of osteoarthritis: a systematic
quality assessment and meta-analysis. JAMA 2000;283:1469-75.
12. Richy F, Bruyere O, Ethgen O, Cucherat M, Henrotin Y,
Reginster JY. Structural and symptomatic efficacy of glucos-
amine and chondroitin in knee osteoarthritis: a comprehensive
meta-analysis. Arch Intern Med 2003;163:1514-22.
13. Towheed TE, Maxwell L, Anastassiades TP, et al. Glucos-
amine therapy for treating osteoarthritis. Cochrane Database
Syst Rev 2005;2:CD002946.
14. Leeb BF, Schweitzer H, Montag K, Smolen JS. A metaanalysis
of chondroitin sulfate in the treatment of osteoarthritis. J Rheu-
matol 2000;27:205-11.
15. Michel BA, Stucki G, Frey D, et al. Chondroitins 4 and 6
sulfate in osteoarthritis of the knee: a randomized, controlled
trial. Arthritis Rheum 2005;52:779-86.
16. Reginster JY, Deroisy R, Rovati LC, et al. Long-term effects
of glucosamine sulphate on osteoarthritis progression: a random-
ised, placebo-controlled clinical trial. Lancet 2001;357:251-6.
17. Pavelka K, Gatterova J, Olejarova M, Machacek S, Giacovelli
G, Rovati LC. Glucosamine sulfate use and delay of progression
of knee osteoarthritis: a 3-year, randomized, placebo-controlled,
double-blind study. Arch Intern Med 2002;162:2113-23.
18. Lequesne M. Symptomatic slow-action anti-arthritic agents:
a new therapeutic concept? Rev Rhum Ed Fr 1994;61:75-9. (In
French.)
Copyright 2006 Massachusetts Medical Society.
to a relatively small number of postmenopausal
women selected because they had low bone min-
eral density on the basis of dual-energy x-ray ab-
sorptiometry results.
RANKL, a member of the tumor necrosis fac-
tor superfamily of ligands and receptors, is essen-
tial for the differentiation, activation, and survival
of bone-resorbing osteoclasts.4 It is expressed
on the surface of marrow stromal cells, activated
T cells, and precursors of bone-forming osteo-
blasts (Fig. 1).4 RANKL accelerates osteoclasto-
genesis when it binds to its receptor, RANK, on
osteoclast precursor cells to enhance nuclear fac-
tor-B and other signaling pathways.4 Osteopro-
tegerin that is produced by osteoblasts, the key
modulator of RANKL, acts as a soluble decoy re-
ceptor for RANKL and blocks its effects.4 McClung
et al. report that denosumab, mimicking the func-
tion of osteoprotegerin, caused especially rapid,
potent, dose-dependent decreases in biochemical
february 23, 2006
 editorials

RANK
OPG Denosumab

RANKL
Osteoclast
precursor Osteoblastic
stromal cell

Osteoclastogenesis

Activated
T cell

Resorption
products

RANKL

Bone
Osteoclast Migration
and apoptosis

Figure 1. The Skeletal Action of Denosumab.

RANKL, a member of the tumor necrosis factor superfamily of ligands and receptors, promotes the differentiation,
activation, and survival of bone-resorbing osteoclasts. Osteoprotegerin (OPG) that is produced by osteoblasts, the
key modulator of RANKL, acts as a natural soluble decoy receptor for RANKL and blocks its effects. Denosumab func-
tions like OPG and has the effect of decreasing osteoclastogenesis, as revealed by diminished biochemical markers of
bone resorption.

markers of bone resorption, as determined by cated an overall reduction in skeletal remodeling.

levels of serum and urine telopeptide products Ideally, an inhibitor of RANKL would not sup-
of bone-collagen degradation. Subsequent decre- press bone formation, but compensatory decreas-
ments in serum bone-specific alkaline phospha- es in bone accretion can follow potent antire-
tase, a marker of osseous tissue formation, indi- sorptive therapy.5

n engl j med 354;8 www.nejm.org february 23, 2006 861

The New England Journal of Medicine

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Copyright 2006 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
Denosumab increased bone mineral density
at one year, especially in the lumbar spine, and
there were slight gains in the total hip and distal
radius that seemed somewhat greater than were
the responses to standard weekly 70-mg doses
of alendronate taken orally in a parallel study
group. The 30-mg and 60-mg doses of denosum-
ab administered at intervals of every three or
six months, respectively, appear to be most ap-
propriate for further clinical trials, on the basis
of the present report. McClung et al. emphasize
the appeal of denosumab because of its pro-
longed bone antiresorptive action.3
Targeting RANKL for deactivation makes sense
as a way to prevent or to treat many types of bone
loss.6 Conditions that may potentially benefit from
RANKL inhibition include not only various types
of osteoporosis but also multiple myeloma, met-
astatic bone disease, humoral hypercalcemia of
malignancy, hyperparathyroidism, and other con-
ditions, particularly those featuring RANKLosteo-
protegerin dyssynergy. Testing of recombinant
osteoprotegerin preceded the evaluation of deno-
sumab, but osteoprotegerin seems to have fallen
by the wayside, partly because neutralizing anti-
bodies to it could develop in patients.6
Long-acting doses of denosumab should en-
hance our pharmaceutical arsenal for the treat-
ment of osteoporosis by improving convenience
and compliance for some patients.2 However, this
issue is also being addressed by the availability
of increasingly potent antiresorptive bisphospho-
nates. Alendronate, risedronate, and ibandronate
were marketed with administration schedules that
increasingly simplified oral therapy from once
daily, to weekly, to monthly. Another advanced-
generation bisphosphonate, zoledronic acid, is
being tested in the form of a brief intravenous
infusion administered yearly.5
Anti-RANKL treatment represents a novel an-
tiresorptive therapy. However, one concern with
this approach is that denosumab could glob-
ally disrupt the signaling pathway that involves
RANKL, osteoprotegerin, RANK, and nuclear fac-
tor-B. RANK is expressed on cells other than os-
teoclast precursors, including dendritic cells and
T and B cells.4 RANKL not only regulates osteo-
clastogenesis but also functions within the im-
mune system.7 The effects of denosumab could
differ from those of the bisphosphonates, the
selective estrogen-receptor modulator raloxifene,
and salmon calcitonin (all three of which are
862 n engl j med 354;8
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of m e dic i n e
approved for the treatment of some forms of os-
teoporosis). In the study by McClung et al., there
was a 1.9 percent incidence of neoplasm and a
1.0 percent incidence of unspecified infection
in the denosumab groups, although these oc-
currences were not statistically significant. Nei-
ther of these problems developed in subjects in
the placebo group or the alendronate group af-
ter 12 months, but both of these groups were
smaller than the group that received denosumab.
Although tumor necrosis factors and differ
structurally from RANKL, pharmaceutical agents
that inhibit these molecules engender concern
about the potential development of infections,
tumors, and hematologic and immune dysfunc-
tion.7 Accordingly, larger and longer clinical tri-
als of denosumab for the prevention of osteopo-
rotic fracture must search for these potential
complications.
Because inhibition of RANKL blocks osteo-
clastogenesis and osteoclast action, the increas-
es in bone mineral density after treatment that
are reported by McClung et al. would reflect a
filling of bone-resorption spaces by osteoblasts.
As bone mass is then preserved, further incre-
ments in bone mineral density might not occur
with continued treatment.8 Recently, bone anti-
resorptive bisphosphonates, especially pamidro-
nate and zoledronic acid, have been associated
with osteonecrosis of the maxilla and mandi-
ble,9 particularly after tooth extraction and in per-
sons who have been treated with corticosteroids
or chemotherapy. Thus, there is concern that ady-
namic bone disease (frozen bone) could result
from excessive suppression of bone remodeling
and lead to fracture.8
McClung et al. demonstrate that denosumab
can cause rapid and potent suppression of bone
resorption and that this suppression seems to be
reversible. Perhaps short-acting bone antiresorp-
tive agents (e.g., lower doses of denosumab), co-
ordinated with anabolic agents for bone, might
best augment skeletal mass and improve bone
quality while preventing depressed skeletal turn-
over.10 Denosumab, at doses that are relatively
short-acting, may be a promising match for some
anabolic agents, such as human recombinant para-
thyroid hormone (1-34) (teriparatide) and the para-
thyroid hormone (1-84) molecule presently under-
going clinical evaluation.11 Bone anabolic and
antiresorptive agents together in optimal doses
and sequences might further uncouple bone turn-
www.nejm.org february 23, 2006
 editorials

over in favor of progressive and greater bone ac-
cretion, but the complexity of such regimens would
increase the risk of poor compliance in some pa-
tients.
Therapy for osteoporosis is increasingly be-
ing tailored to treat specific clinical situations
and to enhance compliance with medical therapy.
Denosumab is a promising antiresorptive treat-
ment that may play a role in both the long and
the short of bone therapy.
No potential conflict of interest relevant to this article was
reported.
From the Center for Metabolic Bone Disease and Molecular Re-
search, Shriners Hospital for Children, St. Louis.
1. Office of the Surgeon General. Bone health and osteoporo-
sis: a report of the Surgeon General. Rockville, Md.: Department
of Health and Human Services, 2004.
2. Solomon DH, Avorn J, Katz JN, et al. Compliance with oste-
oporosis medications. Arch Intern Med 2005;165:2414-9.
3. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in
postmenopausal women with low bone mineral density. N Engl
J Med 2006;354:821-31.
4. Martin TJ. Paracrine regulation of osteoclast formation and
activity: milestones in discovery. J Musculoskelet Neuronal Inter-
act 2004;4:243-53.
5. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zole-
dronic acid in postmenopausal women with low bone mineral
density. N Engl J Med 2002;346:653-61.
6. Kostenuik PJ. Osteoprotegerin and RANKL regulate bone
resorption, density, geometry and strength. Curr Opin Pharma-
col 2005;5:618-25.
7. Walsh MC, Kim N, Kadono Y, et al. Osteoimmunology:
interplay between the immune system and bone metabolism.
Annu Rev Immunol (in press).
8. Ott SM. Long-term safety of bisphosphonates. J Clin Endo-
crinol Metab 2005;90:1897-9.
9. Woo S-B, Hande K, Richardson PG. Osteonecrosis of the jaw
and bisphosphonates. N Engl J Med 2005;353:100.
10. Heaney RP, Recker RR. Combination and sequential therapy
for osteoporosis. N Engl J Med 2005;353:624-5.
11. Black DM, Bilezikian JP, Ensrud KE, et al. One year of alen-
dronate after one year of parathyroid hormone (184) for osteo-
porosis. N Engl J Med 2005;353:555-65.
Copyright 2006 Massachusetts Medical Society.

COLLECTIONS OF ARTICLES ON THE JOURNALS WEB SITE

The Journals Web site (www.nejm.org) sorts published articles into
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