Title: PharmaNote
Full Citation
Permanent Link: http://ufdc.ufl.edu/UF00087345/00090
 Material Information
Title: PharmaNote
Physical Description: Serial
Language: English
Publisher: College of Pharmacy
Place of Publication: Gainesville, Fla.
Publication Date: October 2010
Copyright Date: 2010
 Record Information
Bibliographic ID: UF00087345
Volume ID: VID00090
Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.

Full Text

Pharma o e'


phonates have become the most common treat-
ment for osteoporosis By 2006, an estimated
190 million prescriptions have been written in the
United States for oral alendronate, risedronate, and
ibandronate and more than 6 million patients have
been treated with IV bisphosphonates for cancer
worldwide.2 All bisphosphonates reduce osteoclastic
bone resorption.
Bisphosphonates are approved for the treatment
and/or prevention of osteoporosis, Paget's disease,
hypercalcemia, heterotopic ossification, osteolytic me-
tastases and multiple myeloma (Table 1). Based on
side chain properties, bisphosphonates are catego-
rized as either nitrogen containing or non-nitrogen
containing [Table 2). Nitrogen-containing bisphos-
phonates inhibit bone resorption 100 to 10,000 times
more than the non-nitrogen containing etidronate.3
The older, non-nitrogen containing bisphosphonates
create poisonous analogs of ATP causing osteoclastic
death." The newer nitrogen-containing bisphospho-
nates are presently the most extensively used in prac-
tice and work to inhibit farnesyl pyrophosphate syn-
thase (FPPS), reducing osteoclast activity and promul-
gating apoptosis.


Physiologic strains on bone continually generate

fatigue microdamage which activates bone remodel-
ing, an essential component of bone mechanics.s Criti-
cal to bone remodeling and repair are the osteclasts,
which serve to break down damaged bone. By inhibit-
ing the activity of osteoclasts, the process of bone re-
modeling is disrupted and microcracks are not re-
Several studies in dogs demonstrated bisphospho-
nates are associated with microcracks and inhibition
of bone remodeling. In 2001, Mashiba et al evaluated
the effects of reduced bone turnover on microdamage
accumulation and toughness of the trabeculae of the
vertebrae and iliac crest in beagles for 1 year.6 The
dogs received alendronate or residronate at 6 times
the expected clinical dose. After 12 months, micro-
damage was significantly increased at all sites meas-
ured. Although the bisphosphonates significantly in-
creased strength of the L-1 vertebra measured by a
compression test, analysis of vertebral mechanical
properties normalized for bone mass and shape
showed tissue toughness was 21% lower in both the
risedronate and alendronate-treated groups as com-
pared with control. The reduction in vertebral tough-
ness reached significance when risedronate and alen-
dronate groups were pooled in a post-hoc fashion. In
2005, a study in beagles by Allen et al demonstrated
risedronate and alendronate at clinical doses can sup-




INDEX FOR VOLUME 25 (OCT. 2009 SEP 2010)

am .

Volume 26, Issue 1 October 2010



Melissa Gibbs, Pharm.D. candidate

Table 1 I FDA-approved indications for selected bisphosphonates.
Postmenopausal Paget's Hyper- Heterotopic Osteolytic Multiple
Osteoporosis Disease calcemia Ossification Metastases Myeloma
Alendronate J J J J

Table 2 I Structural classification of bisphosphonates available in the U.S. and year of 1st FDA approval.

Generic Brand Approved Generic Brand Approved

Etidronate Didronel a 1977 Alendronate Fosamax 1995
Tiludronate Skelid a 1997 lbandronate Boniva a 2003
Pamidronate Aredia a 1991
Risedronate Actonel s 1998
Zoledronate Reclasts; Zometae 2002

Ph.,ni* N V l 26 I,,, 1 O b 2010i l



Risedronate J
Zoledronate J
P= prevention; T= treatment.

press remodeling and increase microdamage after 1
year of treatment.' These studies suggest bisphospho-
nates inhibit bone remodeling and increase microdam-
age, reducing the toughness and intrinsic material
properties of some types of bone.

series was not adequate to prove a causal association.
From 2004 to 2006, several case reports emerged
linking lower-dose bisphosphonates to ONJ.11,12 Still,
most patients in these reports had cancer, introducing
the likelihood for confounding bias by other ONJ asso-
ciated treatments.
In light of the possible association between
bisphosphonates and ONJ, in September of 2004, "Dear
Doctor" letters were sent out describing labeling
changes to two medications including cautionary
statements about ONJ developmental In 2005, the FDA
released a warning about ONJ for all bisphosphonates,
including oral products."
In 2009, a retrospective review performed in Den-
mark reviewed 53 patients with malignancy [median
age 69 years) treated with bisphosphonates during a 5
year period. Two cases of ONJ were registered. In the
first case, the patient developed ONJ spontaneously,
while the second patient acquired symptoms after a
dental procedure's
Based on case reports and reviews, ONJ may be
more common in cancer patients. The incidence of ONJ
in cancer patients receiving high doses of IV bisphos-
phonates on frequent dosing schedules is estimated to
be as high as 1 to 10 per 100 patients.l6 High doses, IV
administration, presence of malignancy and use of
concomitant medications such as steroids and chemo-


The American Society for Bone and Mineral Re-
search defines osteonecrosis of the jaw (ONJ) as the
presence of exposed bone in the maxillofacial region
that does not heal within 8 weeks after identification
by a health care professional.8 In contrast, the Ameri-
can Association of Oral and Maxillofacial Surgeons de-
fines ONJ as the persistence of exposed bone in the
oral cavity, despite adequate treatment for 8 weeks,
without local evidence of malignancy and without
prior radiotherapy to the affected region.g ONJ typi-
cally presents as exposed white or yellow hard bone,
with or without pain, usually following invasive dental
procedures such as tooth extraction or in persons with
poorly fitting dentures.
The first report associating bisphosphonates with
ONJ appeared in 2003 in a case series of 36 patients
treated with IV pamidronate and zolendronate for
skeletal complications of malignancy at 10 times the
doses used to treat osteoporosis.'0 However, the case

oume ssue cto er

ra ma ote

Table 3 I Summary of ADA/AAOMS guidelines for patients undergoing oral or maxillofacial surgery.lg
Bisphosphonate Related ONJ Risk Recommendations
SNo alteration or delay in the planned oral or maxillofacial surgery is neces-
On oral bisphosphonate < 3 years +
-Monitoring patients for ONJ
no clinical risk factors
-Considering alternate dosing of the bisphosphonate, drug holidays, or an
alternative to bisphosphonate therapy

On oral bisphosphonate < 3 years + Consider discontinuation of the oral bisphosphonate for at least 3 months
concomitant steroids, or > 3 years f concomi- prior to oral surgery
tant steroids Bisphosphonate should not be restarted until osseous healing has occurred

to undergo oral or maxillofacial surgery is described
below [Table 3). Health care providers should be cau-
tious of these guidelines as not all recommendations
are evidenced based and rely heavily on clinical ex-
The comprehensive review published by the
American Society for Bone and Mineral Research Task
Force may also be helpful to practitioners.l6 The re-
view stresses the importance of good dental hygiene
for bisphosphonate treated patients and discourages
invasive dental procedures, especially in cancer pa-
tients treated with high-dose IV bisphosphonates. No
evidence states discontinuing injectable bisphospho-
nates before dental procedure will reduce the risk of
ONJ.20 UnfOrtunately, data is lacking to help clinicians
determine the appropriate length of time a patient
should be off the bisphosphonate prior to invasive
dental procedure.


Although bisphosphonates have been proven to
reduce fractures due to osteoporosis, a link between
bisphosphonates and atypical low-impact femoral
fracture has been suggested in several case reports.
The first report to suggest a link between atypical
low-impact femoral fracture and bisphosphonates was
published in 2005. Odvina et al. described 8 post-
menopausal women and 1 man with unusual nontrau-
matic nonvertebral fractures while on alendronate
therapy for 3-8 years.21 FOllowing the publication of
this report, a plethora of case reports emerged relating
bisphosphonates to mid-shaft femur fractures.22-27 A
prOdrome of symptoms typically occur before the frac-
ture including bilateral femur pain, cortical hypertro-
phy, transverse fracture pattern and medial cortical
Retrospective analyses have suggested an associa-
tion between bisphosphonates and atypical femoral
fracture. In 2007, a retrospective study performed in
Singapore reviewed 13 women who presented with

therapy may increase the incidence of bisphosphonate
associated-ONJ. Also, poor dental heath and hygiene
can contribute to development of ONJ.
In contrast to cancer patients, the relative inci-
dence of ONJ in the treatment of osteoporosis patients
is quite low; Rough estimates suggest incidence of 1 in
10,000 to 1 in 100,000 patient years.12 After more
than 60,000 patient years of exposure to nitrogen-
containing bisphosphonates in clinical trials for the
treatment for osteoporosis, including trials with follow
-ups as long as 10 years, ONJ was not observed.17 A
retrospective review of the HORIZON [Health Out-
comes and Reduced Incidence with Zoledronic Acid
Once Yearly) trial evaluated 7,736 women with osteo-
porosis using IV zoledronate for 3 years and revealed
only 2 reports of ONJ, one in the zoledronate group
and one in the control group.l
To date, no prospective, randomized placebo-
controlled trials evaluating a definitive causal relation-
ship between bisphosphonates and ONJ have been
performed, however it is likely ONJ is associated with
bisphosphonate use. Several mechanisms for bisphos-
phonate-induced ONJ have been suggested. First,
bisphosphonates may accumulate in the jawbones as
the jaws are a site of continuous remodeling due to
constant use. In addition, bisphosphonates may hinder
skeletal repair processes to remove necrotic areas as-
sociated with trauma or infection of the jaw bone.
Also, imbalance between osteoblasts and osteoclasts
may cause osteopetrosis ("marble bone"), antiangio-
genesis and inhibition of T cell function, all which may
contribute to ONJ.17 Lastly, bisphosphonates may cre-
ate bony overgrowths blocking the sublingual artery,
leading to decreased circulation near the jaw bone.2
Bisphosphonate treatment guidelines developed
by the American Dental Association (ADA) and the
American Association of Oral and Maxillofacial Sur-
geons (AAOMS) may be helpful to clinicians making
clinical decisions about discontinuing a bisphospho-
nate based upon patient risk stratification.lg A sum-
mary of their recommendations for patients preparing

Volume 26, Issue 1 October 2010


low-energy subtrochanteric fractures, 9 of whom were
on long-term alendronate therapy. 29 The majority of
fractures sustained by the alendronate group were at
the femoral metaphyseal-diaphyseal junction and oc-
curred after minimal trauma. Six of the alendronate
patients experienced prodromal lateral femoral cortex
thickening, 3 of which were bilateral. Five patients re-
ported prodromal pain starting 2 to 6 months before
the femoral fracture whereas none of the non-
alendronate patients reported prodromal symptoms.
This retrospective review is limited by the non-
definitive nature of retrospective analyses and be-
cause patients treated with alendronate were younger
[mean age of 66.9 years) and more active than those
not treated with alendronate (mean age 80.3 years).
The same group from Singapore elaborated on its find-
ings with a retrospective review of 17 postmeno-
pausal women [including the 13 described earlier)
presenting with subtrochanteric insufficiency frac-
tures and taking oral bisphosphonates.so Seventy-six
percent of the patients experienced prodromal pain in
the affected thigh from 1 week to 2 years before the
low-impact fracture.
In 2008, investigators from the Hospital for Special
Surgery in New York City reported 37% of patients
presenting with low-energy subtrochanteric or
diaphyseal fracture were on bisphosphonates. The au-
thors described 15 posmenopausal women receiving
alendronate for a mean of 5.4~ years presenting with
atypical low-impact fractures. Ten of these patients
had simple transverse or oblique fractures with corti-
cal breaking and thickening of the proximal femoral
shaft.31 The group continued to investigate the link
between bisphosphonates and femur fracture in a ret-
rospective review of 70 patients (59 female, 11 male)
with low-impact femoral shaft fractures.32 Thirty-six
percent of the patients were treated with alendronate,
most of them for osteoporosis. Seventy-six percent of
the alendronate users experienced specific transverse,
one-sided breaking of the cortex. Only 1% of the non-
alendronate users experienced this same pattern of
cortical breaking. The odds ratio for this pattern was
139.33 for patients taking alendronate compared to
non-alendronate users.
A 2008 Danish register-based cohort analysis
demonstrated alendronate was significantly associ-
ated with increased risk of atypical subtrochanteric
fractures (2.9/1,000 patient years vs 1.9/1,0000 pa-
tient years in the control).33 These results may be mis-
leading because hip fractures were also significantly
more common in the alendronate group, suggesting
the alendronate users had weaker bones than the con-
trol group at baseline.
Also, a recent retrospective analysis using the re-

sults of three large randomized bisphosphonate trials,
the Fracture Intervention Trial [FIT), the FIT Long-
term Extension [FLEX) trial, and the HORIZON Pivotal
Fracture Trial (HORIZON-PFT), evaluated 12 subtro-
chanteric and diaphyseal femur fractures in 10 pa-
tients, occurring at a rate of 2.3 per 10,000 patient-
years. In each of the three trials, risk of these fractures
for bisphosphonate users was not significantly in-
creased compared to placebo. Although these trials
were randomized, there were not a sufficient number
of events to make definitive conclusions and confi-
dence intervals were wide. Although all of the three
trials excluded concomitant use of corticosteroids,
other antiresorptive medications were allowed in the
cebo-controlled trials studied patients using bisphos-
phonates only 3-4.5 years and could not address
whether the risk of femoral fracture increases as treat-
ment duration is extended. The FLEX trial evaluated
patients using bisphosphonates for 10 years, however
the trial was not placebo-controlled.
One hypothesis suggests the bisphoshpoante-
associated atypical femur fractures are insufficiency
fractures which occur in osteoporostic bone subjected
to normal levels of stress.32 Although the subtro-
chanteric region of the femur is one of the strongest
parts of the femur, such fractures may result from in-
hibited stress fracture repair by bisphosphonates. The
relationship between bisphosphonates and femur
fractures are thought to be due to long term suppres-
sion of bone remodeling leading to increased skeletal
fragility. Minimal trauma is then required to produce
a completed fracture. Case reports also suggest risk
factors may be associated with these low-impact frac-
tures such as concomitant corticosteroid use.25,35
Overall, it appears the risk of subtrochanteric or
diaphyseal femur associated with bisphosphonate use
is extremely low, even in women with osteoporosis
who received bisphosphonates for up to 10 years.
However, according to the National Osteoporosis
Foundation [NOF) Clinical Update of 2008, a 5-year
drug holiday after alendronate use (5-10mg/day) for 5
years does not increase fracture risk and might be ad-
vantageous.36 Moreover, they conclude women at high
risk of vertebral fractures may reasonably continue
alendronate for 10 years. The 2010 NOF Clinician's
Guide to Prevention and Treatment of Osteoporosis
does not discuss the recommended duration of treat-
ment for bisphosphonates.37 However, they do imply
bisphosphonates should be withheld from postmeno-
pausal women with osteopenia and should be saved
for those with osteoporosis. The North American
Menopause Society (NAMS) believes current evidence
does not support recommendations regarding the op-

Volume 26, Issue 1 October 2010


timal duration of bisphosphonate therapy.38 Further
randomized prospective studies must be conducted
before recommendations can be made describing the
optimal duration of bisphosphonates.

6. Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston
CC, et al. Effects of suppressed bone turnover by
bisphosphonates on microdamage accumulation and
biomechanical properties in clinically relevant skeletal
sites in beagles. Bone 2001;28:524e31.
7. Allen MR, Iwata K, Phipps R, Burr D. Risedronate and
alendronate similarly suppress remodeling and in-
crease microdamage in beagles after 1 year of treat-
ment at clinical doses. J Bone Miner Res 2005;
8. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, et
al. Bisphosphonate-associated osteonecrosis of the jaw:
report of a task force of the American Society for Bone
and Mineral Research. J Bone Miner Res 2007;22
9. American Association of Oral and Maxillofacial Sur-
geons position paper on bisphosphonate-related os-
teonecrosis of the jaws. J Oral Maxillofac Surg 2007;
10. Marx RE. Pamidronate (Aredia) and zoledronate
(Zometa) induced avascular necrosis of the jaws: a
growing epidemic. J Oral Maxillofac Surg 2003;61
11. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Os-
teonecrosis of the jaws associated with the use of
bisphosphonates: a review of 63 cases. J Oral Maxillofac
Surg 2004;62(5):527-34.
12. Woo SB, Hellstein JW, Kalmar JR Narrative [corrected]
review: bisphosphonates and osteonecrosis of the jaws.
Ann Intern Med 2006;144([10): 753-61.
13. Hohnecker JA. Dear Doctor Letter Zometa@ (zoledronic
acid) Injection and Aredia@ (pamidronate disodium)
Injection. U.S. Food and Drug Administration Office of
Drug Safety. Available at http://www.fda.gov/ohrms/
dockets/ac/05/briefing/2005-4095B2_02_10 -oats
Zometa-App-9.pdf. March 4, 2005. Accessed May 10,
14. U.S. Food and Drug Administration Office of Drug
Safety: Postmarketing Safety Review. May 6, 2004.
Available at: www.fda.gov/ohrms/dockets/ac/05/
briefing/2005-4095B2_03_04-FDA-TAB3.pdf. Accessed
May 10, 2006.
15. Haidar A, Jmnler M, Folkmar TB, Lund L. Bisphospho-
nate (zoledronic acid)-induced osteonecrosis of the jaw.
Scand J Urol Nephrol 2009;43(6):442-4.
16. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-
associated osteonecrosis of the jaw: report of a task
force of the American Society for Bone and Mineral Re-
search [editorial]. J Bone Miner Res 2007;22([10): 1479-
17. Bilezikian JP. Osteonecrosis of the jaw: Do bisphospho-
nates pose a risk? N Engl J Med 2006;355(22):2278-81.
18. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, et al.
Once-yearly zoledronic acid for treatment of postmeno-
pausal osteoporosis. N Engl J Med 2007;356(18):1809-
19. Advisory Task Force on Bisphosphonate- Related Oste-
nonecrosis of the Jaws, American Association of Oral
and Maxillofacial Surgeons. Position paper on bisphos-


By inhibiting bone remodeling, bisphosphonates
may prevent the repair of microcracks in bone, leading
to adverse skeletal effects such as ONJ, low-impact
femoral fracture and bone pain. Although no definitive
data exists to suggest bisphosphonates are directly
causative of ONJ, a relationship does appear likely, es-
pecially in cancer patients treated with high-dose IV
bisphosphonates. However, the risk for ONJ in patients
treated with lower-dose oral bisphosphonates for os-
teoporosis appears to be relatively low. Patients are
encouraged to maintain good oral hygiene but to avoid
invasive dental procedures, especially in those at high
risk for ONJ. No evidence exists to suggest discon-
tinuation of injectable bisphosphonates before dental
procedure will reduce risk of ONJ, however it may be
considered. The risk of subtrochanteric or diaphyseal
femur associated with bisphosphonate use is ex-
tremely low, even in women with osteoporosis who
received bisphosphonates for up to 10 years. Current
evidence is lacking on the recommended duration of
bisphosphonate therapy to avoid atypical low-impact
femoral fractures. After 5 years of continuous bisphos-
phonate use, a 5 year drug-holiday may be advanta-
geous in patients at low risk for vertebral fractures.
However, the benefits of continuing alendronate for
10 years may outweigh the risks for patients at high
risk for vertebral fracture.


1. Stafford RS, Drieling RL, Hersh AL National trends in
osteoporosis visits and osteoporosis treatment, 1988-
2003. Arch Intern Med 2004;164(14):1525-30.
2. Watts NB, Diab DL. Long-Term Use of Bisphosphonates
in Osteoporosis. J Clin Endocrinol Metab 2010;95
3. Kennel KA, Drake MT. Adverse effects of bisphospho-
nates: implications for osteoporosis management. Mayo
Clin Proc 2009;84(7):632-7.
4. Frith JC, Mbnkkbnen J, Blackburn GM, Russell RG,
Rogers MJ. Clodronate and liposome-encapsulated clo-
dronate are metabolized to a toxic ATP analog, adeno-
sine 5' (p, y-dichloromethylene) triphosphate, by mam-
malian cells in vitro. J Bone Miner Res 1997;12(C9):1358
5. Martin RB. Fatigue microdamage as an essential ele-
ment of bone mechanics and biology. Calcif Tissue Int

Volume 26, Issue 1 October 2010


-term treatment with alendronate: clues to the
mechanism of increased bone fragility. J Bone Miner
Res 2009;24(10):1736-40.
36. Update on Bisphosphonates FDA-Approved for Preven-
tion and Treatment of Osteoporosisos. National Osteo-
porosis Foundation. June, 2008. Available at: http://
Approved/Clinical_Newsletter_Spring08_V7.pf Ac-
cessed May 10, 2010.
37. Clinician's Guide to Prevention and Treatment of Osteo-
porosis. National Osteoporosis Foundation. 2008.
Available at: http://www.nof.org/professionals/pdfs/
NOF_ClinicianGuide2 009_v7.pdf. Accessed May 2 0,
38. Management of osteoporosis in postmenopausal
women: 2010 position statement of The North Ameri-
can Menopause Society. Menopause 2010;17(1):25-54.


Crystal R. Mason, Pharmn.D. candidate

ype I Diabetes Mellitus [TIDM) is an autoim-
mune disorder in which more than 90% of in-
sulin producing islet cells are destroyed TIDM
affects over one million Americans, accounting for 5-
15% of all patients diagnosed with diabetes. Approxi-
mately 30,000 new diagnosed cases of TIDM occur
each year.2
Lack of natural insulin production requires exter-
nal insulin administration. Conventionally, insulin is
delivered parenterally. Because of the invasive nature
of administration, patients and their providers have
attempted to keep the number of daily injections to a
minimum. However, the landmark Diabetes Control
and Complications Trial (DCCT), published in 1993,
established that intensive insulin therapy (IIT), by
means of multiple daily injections [MDI; three or more
insulin injections/day) or continuous subcutaneous
insulin infusion (CSII; insulin pump therapy), signifi-
cantly decreased complications arising from uncon-
trolled blood glucose (BG) levels. Such complications
include nephropathy, neuropathy, and retinopathy
(risk decreased by 50%/, 60%/, and 76%, respectively.)
3"Additionally, in the EDIC study, a follow-up to the

phonate-related osteonecrosis of the jaws. J Oral Maxil-
lofac Surg 2007;65(3):369-76.
20. Durie BG, Katz M, Crowley J. Osteonecrosis of the jaw
and bisphosphonates. N Engl J Med 2005;353(1):99-
21. Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk
FA, et al. Severely suppressed bone turnover: a
potential complication of alendronate therapy. J Clin
Endocrinol Metab 2005;90(3):1294-301.
22. Schneider JP 2006 Should bisphosphonates be contin-
ued indefinitely? An unusual fracture in a healthy
woman on long-term alendronate. Geriatrics 2006;61
23. Lee P, van der Wall H, Seibel MJ. Looking beyond low
bone mineral density: multiple insufficiency fractures in
a woman with post-menopausal osteoporosis on
alendronate therapy. Endocrinol Invest 2007;30([7):590
24. Imai K, Yamamoto S, Anamizu Y, Horiuchi T. Pelvic in-
sufficiency fracture associated with severe suppression
of bone turnover by alendronate therapy. J Bone Miner
Metab 2007;25(5):333-6.
25. Odvina CV, Levy S, Rao S, Zerwekh JE, Rao SD Unusual
mid-shaft fractures during long term bisphosphonate
therapy. Clin Endocrinol (Oxf). 2010;72(C2):161-8.
26. Lee P, Seibel MJ. More on atypical fractures of the femo-
ral diaphysis. N Engl J Med 2008;359(3):317-18.
27. Armamento-Villareal R, Napoli N, Panwar V, NovackD.
Suppressed bone turnover during alendronate therapy
for high-turnover osteoporosis. N Engl J Med 2006;355
28. Capeci CM, Tejwani NC. Bilateral low-energy simu-
lateneous or sequential femoral fractures in patients on
long-term alendronate. J Bone Joint Surg Am 2009;91
29. Goh SK, Yang KY, Koh JS, Wong MK, Chua SY, et al.
Subtrochanteric insufficiency fractures in patients on
alendronate therapy: a caution. Bone Joint Surg Br.
30. Kwek EB, Goh SK, Koh JS, Png MA, Howe TS. An emerg-
ing pattern of subtrochanteric stress fractures: a long-
term complication of alendronate therapy? Injury.
31. Lenart BA, Lorich DG, Lane JM. Atypical fractures of the
femoral diaphysis in postmenopausal women taking
alendronate. N Engl J Med 2008;358(12):1304-6.
32. Neviaser AS, Lane JM, Lenart BA, Edobor-0sula F, Lorich
DG. Low-energy femoral shaft fractures associated with
alendronate use. J O rthop Trauma 2 008;2 2(5):346-5 0.
33. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and
diaphyseal femur fractures in patients treated with
alendronate: a register-based national cohort study. J
Bone Miner Res 2009;24(6):1095-102.
34. Black DM, Kelly MP, Genant HK, Palermo L, Eastell R.
Bisphosphonates and fractures of the subtrochanteric
or diaphyseal femur. N Engl J Med 2010;362(19):1761-
35. Somford MP, Draijer FW, Thomassen BJ, Chavassieux
PM, Boivin G, et al. Bilateral fractures of the femur
diaphysis in a patient with rheumatoid arthritis on long

Volume 26, Issue 1 October 2010


DCCT trial published in 2005, it was found that IIT also
reduced the risk for cardiovascular disease by 42%/,
and the composite incidence of nonfatal heart attack,
stroke, or death from cardiovascular causes by 57%.s
For many participants, especially those whose BG re-
mains uncontrolled with fewer insulin injections, IIT
has become the standard of diabetic care. Though
many participants utilize MDI, an increasing number
of participants and their providers are taking interest
in CSII. The purpose of this review is to evaluate the
advantages and disadvantages of CSII, and compare its
efficacy to that of MDI with regards to management of
Alc in participants with TIDM.


Insulin pumps were introduced as unsightly, bulky
instruments in the late 1970s, and have since evolved
into light, compact machines that have greatly de-
creased the burden of carrying insulin administration
supplies. An insulin pump attempts to mimic normal
pancreatic activity by providing a basal rate of short-
acting insulin [e.g. lispro, aspart) by means of contin-
ual infusions via a cannula through an infusion site,
usually located in the abdominal area.l6 Pumps allow
for variable basal rates during different hours of the
day (ex: 0.5U/hr: 12am-9am, 1U/hr: 9am-3pm, etc).
Pumps also allow for manually controlled bolus doses
when necessary, such as after a meal or snack.
The use of pumps is increasing among older
children (mean age: 14) and adolescents. In an obser-
vational, population-based study in children less than
20 years of age, approximately 47% of 2,743 partici-
pants utilized CSII.7 InSulin pumps were more com-
mon in older children (mean age: 14), non-Hispanic
whites [26.3%; compared to three MDI regimens
(glargine + rapid; glargine + rapid + other; no
glargine) and 1-2 injections per day without glargine],
those of families with higher incomes (30.7%/;
$75,000+/yr), higher parental education (29.5%/;

Table 1 I Advantages and disadvantages of CSII compared with conventional insulin administration.
Advantages Disadvantages
-No injections Cost
-Easier management of DM (improved QOL) Attached to pump 24hrs/day (bothersome)
-More accurate dose delivery Time commitment for initial training of pump use (full day in
-Predictability of short-acting insulin outpatient setting)
SFewer BG level swings DKA if catheter mistakenly detached for hours
SImproved Alc (addressed further in article) Possible weight gain
-Possible pump failure/complications (i.e., cannula kinks, site
infections, irritation and discomfort)',1

BG = blood glucose; DKA = diabetic ketoacidosis; DM = diabetes mellitus; QOL = quality of life.

Ph.,n i* N V l 26 I,,, 1 O b 2010i l

Bachelors degree or higher), and those with private
insurance (25.2%/). These differences significantly dis-
tinguished pump users from those who used injection
therapy. CSII can provide many advantages over MDI
[Table 1).
A wide variety of features allows a patient to select
a pump that is suitable to their needs [Table 2). All
currently available pumps have a maximum basal rate
and bolus limit.
Pump complications exist despite the multiple ad-
vantages of CSII. These complications are especially
prevalent in patients who are not thoroughly in-
structed on proper pump management, or for those
who disregard proper infusion site replacement pro-
cedures. A double-blind crossover randomized control
trial (RCT) in twenty participants found that when the
infusion site was not changed after the recommended
48 hours of use, participants lost control over insulin
administration during days 3-5. 1o Average total daily
insulin dose increased from 48.5 Units (U) on Day 1 to
55.3 U on Day 5 in order to correct for rising BG levels.
Statistically significant increases were still observed in
average daily BG (122.7 mg/dL on Day 2 to 163.9 mg/
dL on Day 5, P<0.05), fasting BG (120.3 mg/dL, 154.5
mg/dL, P<0.05), 2-hour post-prandial BG (114.6 mg/
dL, 172.1 mg/dL, P<0.05), and daily max BG (207.7
mg/dL, 242.8 mg/dL, P<0.05). In addition to disrupt-
ing BG control, infection may occur when an infusion
site is not changed regularly. Two case reports of
Toxic Shock Syndrome due to Staphylococcus aureus
originating at the infusion site have been reported.ll
In addition to complications associated with infu-
sion site management pump failure can occur. In
March 2010, the FDA's General Hospital and Personal
Use Devices Panel met to review reports concerning
16,849 pump-related events, including 310 deaths,
reported between October 2006 and September 2009.
12 COmmonly listed problems included: an "error"
message on the pump screen (5%/), failure of dose de-
livery (3%/), and need for repair (3%/). Reported ef-

oume ssue cto er

ra ma ote

Table 2 I Comparison of commercially-available insulin pump systems.
Pump Model Weight Basal Total Basal Rates/ Bolus Incre- 1U Bolus Water
(Ma nufactu rer) (oz.)a Incrementb PrOfilec mentS/MaXd Duratione Properties'
Medtronic Paradigma 3 patterns, up to 3 ft for
3.5-3.8 0.05U 0.1U/ 25U 40 s
522/722 (Minimed) 48 rates each 30 m
12 each day for
OneTouch Pinge
3.13 0.025U each of 4 basal 0.05U/ 25U User selected 12 ft for 24 h
Accu-Chek Spirits 5 profiles up to 24 0.1to 2.0U/ 8 ft for
4.0 0.1U 5 s
(Disetronic) rates each 25U 60 m
7 programs up to
0.05 to 0.5U/ 8 ft for
Omnipode (Insulet) 4.0 0.05U 24 segments each 40 s
30U 30 m
(30 m increments)
4 profiles up to 48 1 meter for
Amigo" (Nipro) 3.4 0.005U 0.05U/ 30U 5 s
rates each 35 m
DANA Diabecare II/IIS/ 1 profile up to 24
1.8-1.9 0.1U 0.1U/ 80U 12 s watertight
IISG/Ro (Sooil) basal rates
Adapted from: http://www.diabeteshealth.com/media/pdfs/PG004IslnPmsCatDaeeelh21.d
ft =feet; h =hours; m =minutes; sec =seconds, U =units.
"weight based on full battery and cartridge.
Increment at which basal doses may be adjusted.
c number of profiles allowed on each unit, with number of insulin administration schedules programmable per profile.
Increment at which bolus doses may be adjusted.
e time required to deliver 1U of bolus insulin.
'depth and time pump may be submerged in water and remain fully functional.

fects of such problems included hospitalization (21%/),
DKA (8%/), and hyper- or hypoglycemia (8%/ and 5%/,
respectively.) However, most reports were neither
complete nor thoroughly investigated, and 20% were
filed as "problem unknown."
The cost of the pump and its supplies is an impor-
tant issue when considering CSII [Table 3). A pump
and its accessories (dressings, tubing, syringes, and
cartridges) costs approximately $5,000- $6,000 USD. 13
Monthly supplies may cost $500, depending on fre-
quency of site change and brand name.'" Even with
insurance coverage, out-of-pocket expense may be


Multiple clinical trials and meta-analyses have
compared the two forms of IIT in participants with
TIDM [Table 4). According to the 2010 Standards of
Medical Care in Diabetes Guidelines, the American Dia-
betes Association (ADA) recommends a general goal
Alc of <7% in non-pregnant adults.ls Because Alc re-
flects the estimated average glucose over the past
three months, only those trials with a follow-up time
of at least 12 wks were included [unless observational
or select meta-analyses).

Youth-Centered Studies
TIDM is typically diagnosed during early adoles-
cence into young adulthood, and many trials compar-

m:m .

ing CSII and MDI efficacy have been conducted exclu-
sively within this patient population.
DiMeglio, et al. conducted a randomized control
trial of forty-two participants under the age of five,
who had been diagnosed with TIDM for at least one
year, and regularly took insulin injections. 16 Partici-
pants were studied for six months with the primary
endpoint of Alc (measured at baseline, 3 and 6
months), and multiple secondary endpoints, including
severe hypoglycemic episodes, BG variability, BMI,
meter-detected hypoglycemia, and patient satisfaction.
Participants were randomly assigned to receive insu-
lin by means of CSII (lispro via MiniMed 508@) or MDI
[various insulin brands). Thirty-seven participants
completed the study. After three months, CSII was sig-
nificant when compared with MDI groups (8.4~% vs.
8.8%/, P<0.05). However, after six months, the two
groups were comparable (CSII 8.5%/, MDI 8.7%) and
no statistically significant difference was found. Pa-
tient satisfaction with pump therapy resulted in 95%
of families deciding to continue CSII after the study.
The authors found no statistically significant differ-
ences among the secondary endpoints.
A randomized, prospective study by Nabhan, et al.
found that though there was an initial significantly sig-
nificant decrease in Alc between CSII and MDI, Alc
was comparable by the study's end .18 Thirty-five
TIDM participants less than five years of age were ran-
domized to either CSII or MDI treatment for six
months, followed by crossover to the other arm for six

Volume 26, Issue 1 October 2010


Table 3 I Insulin pump and supply costs.
Cost of Cost of 1 month supply Cs Uga fo le dlb
Pump Model (Manufacturer) a .Cs oUgaefo le oe
Pumpa fusion sets (10 sets)a
Model Cost
Medtronic Paradigma 522/722
$5,260 $110-115 715/515 $899
722/522 $799
Model Cost
1220 $599
OneTouch Pinge (Animas) $4,200 $110-134
1250 $399
2020 $299
Time Current Pump
<7mos Free
Accu-Chek Spirite (Disetronic) $4,600 $94
7-12mos $299
13-24mos $399
25-36mos $599
Omnipode (Insulet) $666 $396 $299.99 to switch from other pump to Omnipod

Amigo" (Nipro) Data Unavailable
Data Unavailable
All costs in USD.
a actual cost to patient can be less; prices based on http://www.americandiabeteswholesa le.com/StoreFront.bok.
b upgrade costs attained from manufacturer sites on May 18, 2010.

months. However, due to patient family anxiety in the
initial CSII group of returning to MDI administration,
they were allowed to continue CSII for the following
six months. After six months of CSII therapy, regard-
less of time of initiation, a significant decrease in Alc
was noted (P=0.002). However, overall, there was no
significance between Alc when comparing MDI to CSII
(P=0.518) or when comparing time and group
[ P=0.454).
Conversely, trials in older youth reflected a statis-
tically significant difference in Alc levels when com-
pared to baseline.17 Doyle, et al. conducted a random-
ized, prospective trial on thirty-two CSII-nal've TIDM
participants, aged eight to twenty-one. The primary
endpoint was Alc reduction and the secondary end-
point was total daily dose (TDD) of insulin. Partici-
pants were randomly assigned to receive insulin by
means of CSII [aspart via MiniMed 508@/Paradigm
511@) or MDI (glargine + aspart) for sixteen weeks.
While participants in the MDI group did not have a
significant difference from baseline Alc (8.2%/ vs.
8.1%/, P=0.89), those in the CSII group saw a decrease
in their Alc from 8.1% to 7.2% (P<0.02). TDD was also
significantly less with CSII than MDI (0.9U/kg vs. 1.2
U/kg, P=0.03).
In the SEARCH study, over 2700 participants un-
der the age of twenty were studied.' After adjustment
for sociodemographic and clinical factors, CSII partici-
pants also had a significantly lower Alc. The mean Alc

of CSII participants was 8.0%/, whereas participants
using MDI achieved 8.5% (glargine/rapid insulin),
8.9% (glargine/rapid + other), 8.6% [MDI: no
glargine) and 8.6% [two or less injections + no
glargine) (P<0.0001). Additionally, CSII participants
had a significantly fewer of ER visits (P<0.0001) and
hospitalizations (P<0.0001).

Adult-Centered Studies
As with the youth-centered trials, conflicting
evidence exists as to the efficacy of Alc control when
comparing CSII to MDI in adults with TIDM.
Noninferiority of MDI vs. CSII was demonstrated in
a randomized parallel multi-center study by Bolli, et
al.19 Forty-three participants aged eighteen to seventy
were randomized to CSII (lispro via MiniMed 508@)
or MDI (glargine + lispro), and followed for twenty-
four weeks. All participants were CSII-nal've and previ-
ously used an NPH-based MDI regimen. The primary
outcome was Alc, and secondary outcomes included
BG levels (pre- and postprandial, bedtime and 3am
levels, and within day variability), frequency of hypo-
glycemic episodes, adverse events, costs, and patient
satisfaction. Alc results were similar between CSII and
MDI [ -0.7% vs. -0.6%) and all secondary endpoints
were comparable, with the exception of cost. Including
the cost of the pump and site-change kits, lispro-based
CSII was 3.9 times more costly than MDI ($3722 vs.
$959; at a conversion of 1 Euro= 1.23 USD).

Volume 26, Issue 1 October 2010


Table 4 I Summary of Clinical Trial Comparing Efficacy of CSII and MDI.
Study (year) Design Participant ages (n) F/U Results
Youth-Centered Studies

BG = blood glucose; CSII = continuous subcutaneous insulin infusion; F/U= follow up; MDI = multiple daily injections; mos = months; RCT = randomized controlled
trial; TDD = total daily dose; wks = weeks.

MKlW .

- CSll and MDI comparable
SHigh patient satisfaction with CSll
- CSll decreased Alc more than MDI
- CSll requires less TDD than MDI
-CSll and MDI comparable
CSll participants had a lower mean
Alc than various MDI regimens or
those receiving (P<0.0001)
- CSll participants had less ER visits and
hospitalizations (both P<0.0001)

. similar Alc reduction in CSll and MDI
costs ~4 times more with CSll therapy
significantly lower Alc, mean BG,
TDD of insulin, basal and bolus dose
with CSll
S72.5% preference for CSll continua-
tion post-study

DiMeglio, et al.1s (2004)

Doyle, et al.1 (2004)

Nabhan, et al. (2009)

Paris, et al.7 (2009)

<5 years (n=37)

8-21 years (n=32)

<5 years (n=25)

<20 years (n=2743)

6 mos

16 wks

12 mos

Multicenter observa-
tional population-

Adult-Centered Studies

Bolli, et al. (2009)

Hanairr-Broutin, et al. o

Randomized Parallel

Open-Label Random-
ized crossover

18-70 years (n=43)

21-65 years (n=40)

24 wks

32 wks

Non-Specified Metar-Anarlyses

-lower Alc, rates of severe/nocturnal
5-52 wks hypoglycemia (unknown significance)
in CSll-treated participants
-CSll (both aspart and lispro) signifi-
12+ wks cantly reduces Alc more than MDI in
participants >10yoa

Meta-Analysis (13

Meta-Analysis (11

Meta-Analysis (12

Fatourechi, et al.21(2009)

Monami, et al.22 (2009)

Pickup, et al.l (2002)

1+ years (n=669)

Various (n=833)

Various (n=600)-

2.5 -

Minimal beneficial reduction in Alc,
TDD, mean BG concentration

On the other hand, some studies demonstrate that
CSII is superior to MDI. In an open-labeled, random-
ized crossover trial conducted by Hanairr-Broutin, et
al., forty IIT-nal've TIDM participants were randomized
to CSII (lispro via MiniMed 506/507@ or HTron D/
V@) or MDI [NPH + lispro).20 PartiCipantS used one
method of administration for four months, and then
switched to the other for four months. A significant
difference was found in the primary outcome and all
but one secondary outcome [number of people with
BG <60 mg/dL). At study end, Alc with CSII was less
than MDI (7.89%/ vs. 8.24%, P<0.001). Statistically sig-
nificant differences between CSII and MDI were found
with BG (165 mg/dL vs. 175 mg/dL, P<0.05; respec-

tively), TDD (38.5%/ vs. 47.3%/, P<0.0001), basal insu-
lin dose (20.8 U/day vs. 27.5 U/day, P<0.03), and bo-
lus insulin dose (17.7 U/day vs. 19.8 U/day, P<0.04).
At the end of the study, twenty-nine participants pre-
ferred CSII [21 on CSII last 4 mos; 9 on MDI last 4
mos), while only eleven preferred MDI (1 on MDI last
4 mos; 10 on CSII last 4 mos).

In 2002, a meta-analysis of twelve trials by
Pickup, et al. was published comparing pump therapy
to MDI.1 The study analyzed twelve RCTs from 1975-
2000, with each study lasting 2.5-24 months, and a
combined six hundred TIDM participants were ac-

Volume 26, Issue 1 October 2010


counted for. Primary outcomes were BG concentra-
tions and Alc, with TDD as a secondary outcome. The
standardized mean difference in BG levels between
CSII and MDI was 0.56 (95%/ CI: 0.35-0.77; mean of
1mmol/L), Alc values differed by 0.44 95%/ CI: 0.2-
0.63) (mean 0.5% less with CSII), and between insulin
TDD was 0.58 (95%/ CI: 0.34-0.83) [average 15% TDD
reduction with pump therapy). Overall, pump therapy
was minimally more beneficial than MDI therapy.
In the more recent 2009 meta-analysis by Fatoure-
chi, et al., similar outcomes were seen. 21 This study
focused on those eligible RCTs comparing CSII and
MDI published after the Pickup, et al. meta-analysis
(2002) until March 2008. Thirteen studies (total
n=669) of TIDM participants were analyzed, each
study lasting five to fifty-two weeks. Participants using
CSII vs. MDI had a greater reduction in Alc by 0.2%
(95%/ CI: 0.1-0.3), a finding of unknown clinical signifi-
cance. A statistically nonsignificant advantage was
found with CSII with respect to severe hypoglycemic
episodes (OR 0.48, 95% CI: 0.23-1.0) and nocturnal
hypoglycemia (OR 0.82, 95%CI: 0.33-2.03) in adoles-
cents and adults. However, an increased risk of minor
hypoglycemia in CSII-treated children enrolled in par-
allel studies was present.
In another 2009 meta-analysis, Monami, et al. ana-
lyzed eleven randomized control trials [crossover or
parallel series design) [total n=800+) of TIDM partici-
pants comparing CSII and MDI efficacy.22 All trials
were published before July 2008 and were at least 12
weeks in length. Alc was significantly lower in those
participants with CSII than MDI. CSII reduced Alc by
an average of 0.2% (with lispro, P=0.001) and 0.6%
[with aspart, P=0.002) when compared with MDI. Con-
sistent with the results of the youth-centered trials,
there was a significant reduction in Alc[-0.3%,
P<0.001) in those trials where the average age was
greater than ten, but not in trials of younger children
[-0.1%, P=0.48). Episodes of severe hypoglycemia
were comparable across all age groups.


Type I Diabetes Mellitus affects many people in
America and the appropriate management of their dis-
ease is vital. Studies have shown that IIT provides bet-
ter control of Alc than less intensive therapy. Com-
pared with standard injection therapy, CSII has advan-
tages and disadvantages which should be considered
on a patient-by-patient basis. Several trials suggest
that CSII does not provide significant long-term bene-
fit in young children. However, several studies show
benefit when compared to MDI and support its use in
select adolescents and adults.



1. Triplitt Curtis L, Reasner Charles A, Isley William L.
Chapter 77. Diabetes Mellitus" (Chapter). Joseph T.
DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke,
Barbara G. Wells, L. Michael Posey: Pharmacotherapy: A
Pathophysiologic Approach, 7e. http://
www. accesspharmacy. com.1p. hscl. ufl. edu/
2. Monique Laberge, PhD., Altha Roberts Edgren., and Re-
becca J. Frey, PhD. Diabetes mellitus, type 1. The Gale
Encyclopedia of Medicine. Ed. Jacqueline L. Longe. 3rd
ed. Detroit: Gale, Online update, 2007. 5 vols. Updated
November 2009.
3. The Diabetes Control and Complications Trial Research
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the Development and Progression of Long-Term Com-
plications in Insulin-Dependent Diabetes Mellitus. N
Engl J Med. 1993;329(14):977-86.
4. National Diabetes Information Clearinghouse. DCCT
and EDIC: The Diabetes Control and Complications Trial
and Follow-up Study. NIH Publication No. 08-3874.
May 2008. Available from: http://
5. Diabetes Control and Complications Trial/
Epidemiology of Diabetes Interventions and Complica-
tions (DCCT/EDIC) Study Research Group. Intensive
diabetes treatment and cardiovascular disease in par-
ticipants with type 1 diabetes. New Engl J Med
6. Bradley BA. Insulin Pump Basics: Helping You Under-
stand the Terminology. Jul 1, 2004. http://
www.diabeteshealth.com/read/2 004/07/01/4028/
7. Paris CA, Imperatore G, Klingensmith G, et al. Predictors
of Insulin Regimens and Impact on Outcomes in Youth
with Type 1 Diabetes: the SEARCH for Diabetes in Youth
Study. J Pediatr 2009;155(2):183-9.
8. American Diabetes Association. Insulin Pumps. Avail-
able from: http://www. diab etes. org/living-with-
9. Guilhem I, Balkau B, Lecordier F, et al. Insulin pump
failures are still frequent: a prospective study over 6
years from 2001 to 2007. Diabetologia 2009;52:2662-

10. Thethi TK, Rao A, Kawji H, et al. Consequences of de-
layed pump infusion line change in patients with type 1
diabetes mellitus treated with continuous subcutaneous
insulin infusion. J Diabetes Complications 2010;24:73-8.
11. Tanner MH, Liljenquist JE. Toxic shock syndrome from
Staphylococcus aureus infection at insulin pump infu-
sion sites. Report of two cases. JAMA. 1988;259(3):394-

12. Mechcatie E. Insulin pump problems are mostly user
related. Family Practice News. March 15, 2010;40([5):6

13. Kanakis SJ, Watts C, Leichter SB. The Business of Insulin
Pumps in Diabetes Care: Clinical and Economic Consid-

Volume 26, Issue 1 October 2010


Index for Volume 25 COct 2009 Sep 20101

The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacotherapy and Translational
University of Florida

John G. Gums Editor
PharmD, FCCP

R. Whit Curry, MD Associate Editor

Steven M. Smith Assistant Editor
Ph armD


erations. Clinical Diabetes 2002;20:214-6.
14. Bradley B. Financial Concerns About Insulin Pumps.
Accessed on May 17, 2010 at: http://
www.diabeteshealth.com/read/2 006/02/01/452 7/
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Diabetes--2010. http://care.diabetesjournals.org/
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controlled study of insulin pump therapy in diabetic
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ized, prospective trial comparing the efficacy of con-
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daily injections using insulin glargine. Diabetes Care
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prospective study of insulin pump vs.. insulin injection
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-month glycemic, BMI, and neurocognitive outcomes.
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19. Bolli GB, Kerr D, Thomas R, et al. Comparison of a Multi-
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20. Hanaire-Broutin H, Melki V, Bessieres-Lacombe S,
Tauber JP. Comparison of continuous subcutaneous
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21. Fatourechi MM, Kudva YC, Murad MH, Elamin MB, Tab-
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22. Monami M, Lamanna C, Marchionni N, Mannucci E. Con-
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analysis. Acta Diabetol 2009 [Epub ahead of print].


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Mar 2010 (5)
Nov 2009 (1)
Mar 2010 (1)

Apr 2010 (1)
July 2010 (1)
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May 2010 (1)
Aug 2010 (1)

Oct 2009 (1)
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Acne Vulgaris
Aminoglycosides: QD Dosing
Artemether/lumefantrine (Coartem)
Cycloset@ (IR Bromocriptine)

Depression in the Elderly
Diabetic Peripheral Neuropathy
Dronedarone (Multaq@)

Hypertension: Tx During Pregnancy
Liraglutide (Victoza@)

Pharmacokinetics in Pregnancy
Pitavastatin [Livalo@)
Prasugrel (Effient@)

Saxagliptin (Onglyza@)
Telavancin (Vibativ@)

Ustekinumab (Stelara@)
Valturna@ [aliskiren/valsartan)

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