Content uploaded by Anant kumar Singh
Author content
All content in this area was uploaded by Anant kumar Singh on Jan 26, 2017
Content may be subject to copyright.
SC GOEL, Professor, Department of orthopaedics, Institute of medi-
cal sciences banaras hindu university, Varanasi, 221005, India
Gyanendra Kumar JHA, Birju Manjhi, Senior Resident, institute of
medical sciences banaras hindu university, Varanasi, 221005, India
Anant Kumar Singh, Senior Resident, All India institute of medical
sciences, Raipur, 492099, India
Neeraj Agarwal, Professor, Department of endocrinology, Institute
of medical sciences banaras hindu university, Varanasi, 221005, India
TB Singh, Professor, Department of PSM, Institute of medical sci-
ences banaras hindu university, Varanasi, 221005, India
Correspondence to: Anant Kumar Singh, Senior Resident, De-
partment of Orthopaedic Surgery, All India institute of medical sci-
ences, Raipur, 492099, India
Email: anantsingh37@gmail.com
Telephone: +918120085833
Received: August 31, 2014 Revised: October 3, 2014
Accepted: October 9, 2014
Published online: December 23, 2014
ABSTRACT
AIM: Osteoporosis is a systemic skeletal disorder characterized by
low bone mass and microarchitectural deterioration of bone tissue.
Today, an increasing number of medications are available in order to
treat osteoporosis and reduce fracture risks. However, these agents
are expensive and have adverse effects, such as upper gastrointestinal
irritation and ulceration, constipation, enhanced arterial and venous
thrombosis, etc. The aim of the present study is to study the role of L
arginine in the treatment of osteoporosis.
METHOD: A Total of 180 osteoporotic female with DEXA T-score
<-2.5 and vitamin D level >20ng/mL were selected and divided in
to two study groups, 90 patients in each group. Study group A was
given the test drug L-rginine 2 g, along with vitamin D 600 IU and
calcium 500 mg as supplements similarly group B was given the
comparative drugs Zoledronic acid in the dosage of 5 mg iv stat over
15 min once a year, along with vitamin D 600 IU and calcium 500
mg as supplements. The average BMD in group A before starting the
treatment was compared with BMD 2 yrs after treatment, similarly
in group B BMD before starting the treatment was compared with
BMD 2 yrs after treatment and percentage increase was calculated.
Finally the percentage increased in group A was compared with the
respective of the group B and the result was analysed.
RESULT: On comparing our test drug combined with L-arginine
with the standard drug zoledronic acid IV infusion, we found that
there is no difference in increase in BMD in the two groups. The drug
combined with L-arginine is as good as inj. zoledronic acid in the
treatment of osteoporosis.
CONCLUSION: The Zoledronic acid iv infusion and L-arginine
both increase the bone mineral density of the LS spine and both
are equivalent in efficacy and both can be conveniently be used
in the treatment of osteoporosis in the peri and post menopausal
osteoporotic females.
© 2014 ACT. All rights reserved.
Key words: L arginine; Zolendronic acid; Osteoporosis; DEXA Scan
Goel SC, Jha G, Singh Kumar AK, Agarwal N, Singh TB, Manjhi
B. Role of L arginine in Treatment of Osteoporosis. International
Journal of Orthopaedics 2014; 1(4): 177-180 Available from: URL:
http://www.ghrnet.org/index.php/ijo/article/view/795
INTRODUCTION
Osteoporosis is a systemic skeletal disorder characterized by low
bone mass and microarchitectural deterioration of bone tissue
predisposing to an increased risk for fracture. The number of people
affected by osteoporosis has become more significant worldwide
over the last decade, and is now regarded by the World Health
Organisation as one of the 10 most serious global disease[1,2]. Today, a
number of medications are available to treat osteoporosis and reduce
fracture risks. However, these agents are costly and all have adverse
effects, such as upper gastrointestinal irritation and ulceration,
constipation, and enhanced arterial and venous thrombosis, etc[3].
Some agents even have the potential of increasing fracture incidence
with prolonged treatment (e.g., uoride, bisphosphonate). Essential
amino acids, such as L-Arginine (Arg) and L-Lysine (Lys) are
involved in bone metabolism and growth. Arginine is in fact involved
ORIGINAL ARTICLE
Role of L-arginine in Treatment of Osteoporosis
SC Goel, Gyanendra Kumar JHA, Anant Kumar Singh, Neeraj Agarwal, TB Singh, Birju Manjhi
177
Int Journal of Orthopaedics 2014 December 23 1(4): 177-180
ISSN 2311-5106 (Print), ISSN 2313-1462 (Online)
Online Submissions: http://www.ghrnet.org/index./ijo/
doi:10.6051/j.issn.2311-5106.2014.01.32
© 2014 ACT. All rights reserved.
International Journal of Orthopaedics
10,32.indd 2357 2014/12/22 21:34:34
Goel SC
et al.
L Arginine in osteoporosis
178
© 2014 ACT. All rights reserved.
group B average BMD before treatment was compared with average
BMD after 2 yr of treatment and the percentage increased was
calculated. Finally the percentage increased in group A was compared
with the respectives of group B and the result was analysed.
The result was compared in the two study groups on the basis
of percentage increased in BMD, and was analysed whether the
percentage increased was signicant in each group. Also efcacy of
test drug (L arginine) with respect to standard drug (Zoledronic acid)
which is most potent bisphosphonate and is bench mark in treatment
of osteoporosis was analysed.
The statistical analysis was done using SPSS for Windows version
16.0 software. The mean and standard deviation of the parameters
studied during observation period were calculated for two treatment
groups and compared using Student t test. The critical value of ‘p’
indicating the probability of signicant difference was taken as <0.05
for comparisons.
RESULT
Only 150 patient turned for follow up may be because of poor
literacy in this part of world, with 75 patient of group A and 75
patient from group B.
All the patient were primary osteoporotic female with mean age
of 57 in group A and 59 in group B with no known co-morbidities
(Table 1). The average BMD before treatment in group A and B was
observed to be -3.32 and -3.27 respectively (Table 2).
The average BMD in group A after treatment for 2 yr with daily
dose of test drug 2 g L-arginine was found to be -2.97 while in
group B average BMD after treatment with zolendronic acid yearly
injection for 2 yr was found to be -2.84.
There is signicant difference observed in average BMD before
and after treatment in group A (Table 3), also signicant difference is
present in average BMD before and after treatment of group B (Table
4) but there is no signicant difference in BMD of two groups after
treatment (Table 5 and 6).
both in the synthesis of substrates (polyamine and L-proline)
implicated in collagen synthesis, and in the production of growth
hormone (GH), insulin like growth factor-I (IGF-I) and nitric oxide
(NO). Also L-arginine may inhibit osteoclastic bone resorption by
stimulating endothelial NO release and may stimulate bone formation
by activating the growth hormone-IGF-I axis. Because of this dual
effect on physiological regulators of bone remodeling, L-arginine
has the potential to increase bone formation above bone resorption,
and hence, to increase bone mass. Therefore, the aim of the present
study is to study the role of L arginine in treatment of osteoporosis,
effectiveness of L-arginine in osteoporosis and to compare the
efcacy of L-arginine with bisphosphonates (Zolendronic acid) in the
treatment of osteoporosis.
METHOD
The present study was conducted in the department of orthopaedics,
in collaboration with department of Endocrinology and Metabolism,
from November 2011 to July 2013. The study was approved by
institute ethical committee and Written and informed consent taken
from each and every patient
Selections of the patients
Peri and post menopausal females were selected after the diagnosis
of osteoporosis on the basis of clinical symptoms like low back pain
and X-ray of LS and DL spine showing multiple level biconcave
vertebra.
DEXA scan of LS spine along with preliminary investigations
conducted like complete blood count, random blood sugar, liver
function test, renal function test, serum calcium, serum phosphate,
serum vitamin D for the diagnosis and selections of primary
osteoporotic patients.
Inclusion criteria were: (1) Perimenopausal and postmenopausal
women; (2) Clinical symptoms like low back pain; (3) X-ray of LS
and DL spine showing multiple level biconcave vertebra; (4) DEXA
T-score <-2.5.
Exclusion criteria: (1) Males and premenopausal women; (2)
Therapy with steroids, antiepileptic drugs; (3) serum vitamin D<20
ng/mL; (4) Uncontrolled diabetes; (5) Alcohol, tobacco, smoking; (6)
Hormone replacement therapy; (7) Thyroid and parathyroid disease;
(8) Any other osteoporosis therapy.
It was longitudinal prospective study in which a total of 180
osteoporotic female with symptoms of low back pain and X-ray of
LS and DL spine showing osteoporotic changes with DEXA T-score
<-2.5 and vitamin D level >20 ng/mL were selected and divided in to
two study groups on the basis of standard table of random numbers
(90 patients in each group). Study group A was given the test drug
combined with L-arginine 2 g, along with vitamin D 600 IU and
calcium 500 mg as supplements similarly group B was given the
comparative drugs Zoledronic acid in the dosage of 5 mg iv stat over
15 min once a year, along with vitamin D 600 IU and calcium 500
mg as supplements. During our study, both the study groups were
closely followed for 2 year and parameters like immediate and late
side effect of the drug, improvement in the symptoms of the patients,
compliance to the therapy, any fresh complain during the period
of study related to the disease and the treatment along with cost of
therapy were closely observed.
At the end of study BMD of each and every patient were again
taken and the average BMD before treatment in group A was
compared with average BMD after 2 yr of treatment and percentage
increase in the bone mineral density was calculated. Similarly in
Age
Group 1
Group 2
Table 1 Mean Age Of Group A And B.
Mean±SD
57.45±8.317
59.75±6.909
p value
0.182
BMD_Pre_Therapy
Group A
GroupB
Table 2 Mean BMD Pre Therapy of group A and B.
Mean±SD
-3.36±0.73
-3.25±0.71
p value
0.601
Group A
BMD Pre Therapy
BMD Post Therapy
Table 3 Mean BMD pre and post therapy of group A.
Mean±SD
-3.34±0.73
-2.97±0.69
p value
<0.001
Group B
BMD Pre Therapy
BMD Post Therapy
Table 4 Mean BMD pre and post therapy of group B.
Mean±SD
-3.25±0.71
-2.84±0.65
p value
<0.001
GROUPS
A
B
Table 5 Percentage change in BMD in group A and B.
%INCREASE
11.60%
12.61%
10,32.indd 2358 2014/12/22 21:34:34
179 © 2014 ACT. All rights reserved.
Goel SC
et al.
L Arginine in osteoporosis
On comparing our test drug L-arginine with the standard drug
zoledronic acid IV infusion we found that there is no significant
difference in result with the increase in BMD in the two groups. The
drug L-arginine is as good as inj. zoledronic acid in the treatment of
osteoporosis.
All the patients on L-arginine were satisfied to start with the
therapy as the drug could be orally administered, palatable with the
therapeutic dosage of the drug for the treatment of osteoporosis. 15
patients out 90 patient showed gastric intolerance but that was easily
managed by the modifications of dietary habit, and giving proton
pump inhibitors at the prophylactic dosage, no other side effect was
complained by the patients. There were no fresh complaint in the
patient after the start of therapy, the symptoms like low back pain
and radiculopathy found to be improved after administration of
L-arginine therapy. Cost of therapy also was reasonable. However
out of the 90 patient treated with Zoledronic acid 6 patients had
side effect like fever, myalgia, generalized weakness, paresthesia
and impending doom despite preloading with normal saline prior to
therapy, the symptom was probably due to the transient hypocalcemia
due the effect of the drug and the symptom persisted for 3 to 5 days,
however patients wellbeing gradually improved.
DISCUSSION
Osteoporosis, a metabolic bone disease characterized by low bone
mass and microarchitectural deterioration of bone tissue, leading to
enhanced bone fragility and fracture risk. Osteoporosis is decient
matrix with normal mineralization and there is loss of bone mass but
there is an equivalent loss of matrix and mineral also therefore matrix
to mineral ratio remains normal. The number of osteoporotic fractures
is increasing worldwide, Osteoporotic female with BMD <-2.5 of LS
spine had sustained fragility fracture and were at the increased risk
of getting fracture. There are number of pharmacological and non
pharmacological agents that have been proven to reduce the incidence
of osteoporotic fracture. Treatments option are limited by costs, side
effects, and lack of availability. An inexpensive and widely available
treatment is necessary to alleviate this increase in fractures.
Oral administration of L arginine in pharmacological dosage
induces growth hormone and insulin like growth factor- 1 responses
and stimulates nitric oxide synthesis[4]. Growth hormone and insulin
like growth factor 1 are important mediators of bone turnover
and osteoblastic bone formation, while nitric oxide is inhibitor
of osteoclastic bone resorption[5]. Because of this dual effect on
physiological regulator of bone remodeling, L-arginine could
potentially increase bone formation over resorption and consequently
increase bone mass[6,7]. Also L-arginine, a nitric oxide donor could be
a novel agent that has the potential to inuence both the trabecular
and cortical bones[8].
On the other hand Bisphosphonates, which are the current standard
of care in the treatment of osteoporosis are potent anti resorptive
agent that inhibits osteoclastic activity and Zoledronic acid is the
most potent bisphosphonates currently available for clinical use[9].
Oral bisphosphonates are associated with complicated dosing regimes
along with poor absorption and have the potential for gastrointestinal
tract irritation resulting in poor adherence and persistence. Zoledronic
acid 5 mg once yearly intravenous bisphosphonate is approved for
the treatment and prevention of postmenopausal osteoporosis and
treatment and prevention of glucocorticoid induced osteoporosis.
In woman with osteoporosis an annual treatment of Zoledronic acid
increased lumbar spine bone mineral density with by 6% compared
with baseline. Zoledronic is generally safe and well tolerated with 5
mg and has potential to improve patient compliance with osteoporosis
therapy and consequently, to reduce fracture risk in clinical
practice. Also Zoledronic acid is a preferable alternative to oral
bisphosphonate therapy in patients with polypharmacy, significant
gastrointestinal intolerance or suspected medication noncompliance,
cognitive dysfunction and inability to sit upright.
Several previous clinical studies conrmed that nitrate use has
favorable effects on the skeleton in postmenopausal osteoporosis[10-14].
Adequate supplementation in animals or humans with no precursor
like L-arginine could also be effective in prevention of bone losses.
In addition, the role of combination therapies especially with
the combination of no donors with Bisphosphonates needs to be
investigated.
In our study not much difference is present in percentage increase
of BMD after 2 yr of treatment with test drug (L Arginine ) and
comparative drug (zolendronic acid), which is 11.60 percent in group
A and 12.61 percent in group B. However, increase in BMD with
zolendronic acid was found to be better than the earlier studies[15]
and L-arginine has increased BMD as good as iv zoledronic acid.
However L arginine is safer antiosteoporotic as compared with
bisphosphanates.
In most of the prior studies[16,17] the test drug in postmenopausal
studies that is either bisphosphonates like alendronates, hormone
replacement therapy, selective estrogen receptor modulators are all
compared with the placebo, in contrast we gave our patient with
Larginine and zoledronic acid because it will always be unethical
not to treat peri and post menopausal women with osteoporosis, as
once the patient is diagnosed as osteoporosis they are always at the
high risk of getting fragility fracture, so treating them with placebo is
always a crime.
However some side effect of L-arginine like breathing problems,
chestpain, swelling in the legs, low blood pressure nausea and
bloating can happen at higher doses, however L-arginine at the
dosage of 2 g is safe with mild side effect of gastro intestinal
intolerance. However Zoledronic acid had severe side effect of jaw
osteonecrosis[18]. In our study also some patient did suffer from the
immediate reactions like fever, myalgia, impending doom, transient
hypocalcemia leading to severe distress.
L-arginine a nitric oxide donar has indications in plenty of diseases
like congestive heart failure, high blood pressure, coronary heart
disease, intermittent claudication, erectile dysfunction and male
infertility, improving kidney function in renal transplant, speeds
wound healing, increases blood ow to cold hands and feet in people
with diabetes, hence L-arginine can be easily administered in all these
comorbid osteoporotic patients with synergistic therapeutic effect in
these diseased state as well[19,20].
Osteoporosis and fracture go side by side, L-arginine upregulates
every metabolic pathway to optimise and augment bone healing,
induces strong bone formation by enhancing GH and IGH-1 level,
Enhances callus formation by 30%, induces angiogenesis and
reduces inammatory cytokines IL-6[21]. Analysing all these facts we
can conclude there is role of L-arginine in treatment of osteoporosis
and it can be easily administered in all the peri and post menopausal
osteoporotic females with greater therapeutic value and minimal side
effect prole with satisfactory increase in the bone mineral density
and reducing incidence of fragility fractures, promoting healthy
BMD Post Therapy
Group A
Group B
Table 6 Mean BMD post therapy.
Mean±SD
-2.97±0.69
-2.84±0.65
p value
0.506
10,32.indd 2359 2014/12/22 21:34:35
Goel SC
et al.
L Arginine in osteoporosis
and fracture free life style. However longer follow up with bigger
sample size required for further evaluation of efcacy and potency of
L-arginine in clinical practice.
CONFLICT OF INTERESTS
There are no conicts of interest with regard to the present study.
REFERENCES
1 National Osteoporosis Foundation. Physician’s guide to prevention
and treatment of osteoporosis. Washington, DC; 2003.
2 Lin JT, Lane JM. Osteoporosis: a review. Clin Orthop Relat Res
2004; 425: 126-134
3 Levine JP. Pharmacologic and nonpharmacologic management of
osteoporosis. Clin Cornerstone 2006; 8: 40-53
4 Chevalley T, Rizzoli R, Manen D, Caverzasio J, Bonjour JP.
Arginine increases insulin-like growth factor-I production and
collagen synthesis in osteoblast-like cells. Bone 1998; 23: 103-109
5 Löwik CW, Nibbering PH, van de Ruit M, Papapoulos SE. Inducible
production of nitric oxide in osteoblast-like cells and in fetal mouse
bone explants is associated with suppression of osteoclastic bone
resorption. J Clin Invest 1994; 93: 1465-1472
6 Visser JJ, Hoekman K. Arginine supplementation in the prevention
and treatment of osteoporosis. Med Hypotheses 1994; 43: 339-342
7 VM, Prato A, Messina R, Clementi G. L-Arginine prevents bone loss
and bone collagen breakdown in cyclosporine A-treated rats. Eur J
Pharmacol 2000; 408(3): 323-326
8 Wimalawansa S J. Nitric oxide: novel therapy for osteoporosis.
Expert Opin Pharmacother 2008; 9(17): 3025-3044
9 Michael maricic. The role of Zoledronic acid in the management of
osteoporosis. Clin rheumatol 2010; 29: 1079-1084
10 Wimalawansa SJ. Nitroglycerin therapy is as efficacious as
standard estrogen replacement therapy (Premarin) in prevention of
oophorectomy-induced bone loss: a human pilot clinical study. J
Bone Miner Res 2000; 15: 2240–2244
11 Wimalawansa SJ, De Marco G, Gangula P, Yallampalli C. Nitric
oxide donor alleviates ovariectomy-induced bone loss. Bone 1996;
18: 301-304
12 Wimalawansa S, Chapa T, Fang L, Yallampalli C, Simmons D,
Wimalawansa S. Frequency-Dependent Effect of Nitric Oxide Donor
Nitroglycerin on Bone. J Bone Miner Res 2000; 15: 1119-1125
13 Jamal SA, Hamilton CJ. Nitric oxide donar for the treatment of
osteoporosis. Curr osteoporos rep 2012; 10: 86-92
14 Rejnmark L, Vestergaard P, Mosekilde L. Decreased fracture risk
in users of organic nitrates: a nationwide case-control study. J Bone
Miner Res 2006; 21: 1811-1817
15 Lim R, Zailskas S, Goldsby TU, Lukens C, Muravev R, Dulipsingh
L. Effect of zoledronic acid on bone density and markers of bone
turnover in a community clinic. Conn Med 2013; 77(6): 357-359
16 Robert R R, Davies KM, Dowd RM, Heaney RP. Effect of low-dose
continuous estrogen and progesterone therapy with calcium and
vitamin D on bone in elderly women: randomized controlled trial.
Ann Intern Med 1999; 130: 897-904
17 Abdelazim IA, Abdelrazak KM, Al-Kadi M, Yehia AH, Nusair
BM, Faza MA. Effect of raloxifene hydrochloride on bone mineral
density and bone turnover in Kuwaiti postmenopausal women with
osteoporosis. Arch Osteoporos 2014; 9: 189
18 Mortensen M, Lawson W, Montazem A. Osteonecrosis of the jaw
associated with bisphosphonate use: Presentation of seven cases and
literature review. Laryngoscope 2007; 117(1): 30-34
19 Daly JM, Reynolds J, Thorn A. Immune and metabolic effects of
arginine in the surgical patient. Ann Surg 1988; 208(4): 512-523
20 Cooke JP. Role of nitric oxide in progression and regression of
atherosclerosis. West J Med 1996; 164: 419-424
21 Diwan AD, Wang MX, Jang D, Zhu W, Murrell GAC. Nitric Oxide
Modulates Fracture Healing. J Bone Miner Res 2000; 15: 342-351
Peer reviewers: Laura Scaramuzzo, I.R.C.C.S. Galeazzi
Orthopaedic Institute, Spine Division 1, Via Riccardo Galeazzi 4,
00161 Milan Italy; Emmanouil Brilakis, IASO General Hospital,
Center of Arthroscopy and Shoulder Surgery, 276 Mesogeion
Avenue, 155 62, Cholargos, Athens, Greece.
180
© 2014 ACT. All rights reserved.
10,32.indd 2360 2014/12/22 21:34:35
