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J.Orthopaedics 2007;4(3)e3
Introduction:
Osteoporosis
is characterized by decreased bone mass and increased
susceptibility to fracture. The World Health Organization
defined Osteoporosis in 1994 as a condition in which the bone
mineral density (BMD) is 2.5 SD or more below the mass for young
healthy adults of the same race and gender - also referred to as
a T- score of – 2.5. Those who fall at the lower end of
the normal range (a negative T –score of > 1 SD)
are defined as having low bone density and are considered to be
at increased risk of osteoporosis.
Epidemiology:
By this
definition a quarter of all post- menopausal American
Caucasians, in total 26 million white American women are
regarded as having osteoporosis. Osteoporosis occurs more
frequently with increasing age, as bone tissue is progressively
lost. In women, the loss of ovarian function at menopause
(typically about age 50) precipitate rapid bone loss such that
most women meet the diagnosis criteria for osteoporosis by age
70 to 80. Fractures of distal radius increases in frequency
before age 50 and plateau by age 60, with only a modest
age–related increase thereafter. In contrast, incidence rate
for hip fracture double every 5 years after 70. The rising
burden of those fractures imposes an enormous cost on society
and increases morbidity and mortality. A fracture of the hip is
associated with a reduction of 20% in expected survival. Many
patients become permanently disabled with the proportion who
cannot walk rising from 20% before to 50% after fracture. One
third totally, necessitating institutionalization.
It is therefore, imperative to implementation strategies for
preventing such fractures in the community. The purpose of the
present lecture is to review the pertinent information regarding
the biological characteristics, physiological evaluation,
treatment and prevention of osteoporosis.
Pathophysiology:
Osteoporosis
results from bone loss due to normal age related changes in bone
remodeling as well as extrinsic and intrinsic factors that
exaggerated this process. These changes may be superimposed a
low peak bone mass. Consequently understanding the bone
remodeling process is fundamental to understanding the
Pathophysiology of osteoporosis. The skeleton increases in size
by linear growth and by apposition of new bone tissue on the
outer surface of the cortex. This latter process is called “
modeling “. A process that allows the long bones to adapt in
shape to the stress placed upon them. Bone remodeling has two
primary functions: - A) to repair micro damage within the
skeleton to maintain skeletal strength and B) To supply calcium
from the skeleton to maintain serum calcium.
Remodeling may be activated by micro damage to bone as a result
of excessive or accumulated stress. Acute demands for calcium
involve osteoclast- mediated resorption as well as calcium
transport by osteocytes. Bone remodeling is also regulated by
several circulating hormones, including estrogen, androgens,
vit-D and PTH, as well as locally produced growth factors such
as IGF-I and IGF-II transforming growth factor (TGF) ß
parathyroid hormone related peptide (PTHr P) ILs, prostaglandin
and tumor necrosis factor (TNF). The cytokine responsible for
communication between the osteoblast and osteoclast has been
identified as RANK or osteoprotegerin ligand. The osteoclast
receptor for this protein is referred as RANK. Additional
influences include nutrition (particularly calcium intake) and
physical activity level. The end result of this remodeling
process is that the resorbed bone is replaced by an equal amount
of new bone tissue. Bone remodeling proceeds throughout life and
an imbalance in this process that either enhances resorption or
impairs formation ultimately leads to a net loss of bone mass.
Calcium
Nutrition: - Calcium is an essential mineral that
participates in many important physiological functions. Calcium
requirements change throughout life depending on the activity
and functions of the body as well as on the efficiency of
intestinal absorption. 1,2,3,4 During the adult phase of life,
insufficient calcium intake induces secondary
hyperparathyroidism and an increase in the rate of remodeling to
maintain normal serum calcium levels. PTH stimulates the
hydroxylation of vit-D in the kidney, leading to increased level
of 1, 25-dihydroxy vit- D 1,25(OH) 2 D and inhanced
gastrointestinal calcium absorption.
The
greater the peak bone mass achieved, the better the chance of
avoiding osteoporosis later in life. After peak bone mass
reached, bone loss normally occurs at the rate of 0.3% per year
in man and 0.5% per year in women. A rate of bone loss of 2 to
3% per year (an 8% decrease in trabecular bone and a 0.5%
decrease in cortical bone) begins at the onset of menopause.
This rate continues for a period of 6 to 10 year and then
declines to the rate of 0.5% per year. While all adults lose
bone with age, osteoporosis develops in only 20 to 30% of women
and 10 to 20% of men who are more than sixty-five year old.5, 6
Vit-D:
Vit D plays major role in calcium metabolism.7 Vit-D is
formed from 7- dihydrocholecalciferol in the skin under the
direct stimulation of UV light. The vit-D precursor is converted
to 25 hydroxy vitamin D in the lever before being activated by
further hydroxylation to 1, 25 dihydroxyvitamin-D in the kidneys
in response to parathyroid hormone. 1, 25- dihydroxyvitamin-D
increase absorption of calcium across the gut by maturing the
villus lining cells of the intestine and stimulating them to
produce calcium-binding protein. Active vit-D augments
parathyroid recruitment of osteoclast for bone resorption by
acting as a maturation hormone for the macrophage stem cells.
Parathyroid
hormone: The second prominent hormone in the bone
metabolism is parathyroid hormone. Parathyroid hormone responds
to low ionic calcium levels by stimulating the retention of
calcium and excretion of phosphate by the kidney.
Calcitonin:
Calcitonin is a calcitropic peptide produced in the
Para
follicular cells of the thyroid gland. Calcitonin responds to
elevated serum ionic calcium levels by decreasing the number and
activity of osteoclast.8 Calcitonin also functions as a
neuropeptide and has analgesic effect. Pharmacological activity
primarily decreases bone resorption.
Estrogen:
Young woman who has episodes of amenorrhea or oligomenorrhea
before peak bone mass is attained lose 2% of bone mass per year,
instead of gaining 2 to 4% per year as they would normally. This
loss is estrogen dependent and the bone mass that is lost is not
regained once normal menstrual cycles are resumed.9, 10
Glucocorticoids:
Exogenous administered corticosteroid impair the function
and shorten the life span of osteoblast and contribute to
decreased bone formation. Coticosteroids increase the excretion
of calcium in urine and block the resorption of calcium in gut.
That induces hyperparathyroids. The result is a form of
osteoporosis.11
Thyroid
Hormone: Thyroid hormone increases bone remodeling
with osteoclast activity predominating inducing a net loss of
bone.12
Approach to the pateint :
The evaluation of a patient in whom osteoporosis is suspected
should include a through medical history and physical
examination should be performed to identify risk factors for
osteoporosis.
Risk
for osteoporosis: If the patient has a facture that was not
due to noticeable trauma the clinician first must rule out the
presence of a benign, metastatic or primary malignant bone
tumor. Once a tumor has been excluded, the major causes of such
a fracture include bone-marrow abnormalities, endocrinopathies,
osteomalasia and osteoporosis. The clinician should seek to
identify include early natural or operatatively induced
menopause, prolonged period of amenorrhea, poor nutrition, a
history of limited exercise, genetic factors and a history of
alcohol intake or smoking.
Laboratory
Studies: Laboratory
studies are used to exclude other disease that can cause
osteopenia and to determine the type of osteoporosis.
Imaging studies and the
measurement of bone mineral density
Measurement
of bone mineral density can be used to access the risk of a
fracture with high degree of specificity. There is a 1.5 to
3-fold increase in the fracture rate for each standard deviation
of decrease in bone mineral density.13
Radiograph of the spine demonstrate osteopenia (a radiographic
term for an apparent decrease in bone mass density) only when
30% of the bone mass has been lost. The preferential loss of
horizontal trabeculae in vertebral body gives the remaining
vertebral trabecular a hypertrophic appearance.
Single –beam densitometry can be used to measure bone mass at
the distal third of the forearm.14 The finding at that location
may not correspond with the changes in the spine or the hip.
CT
scanning can be used to exmine a window within the vertebral
body as well as to measure the trabecular bone mass therin.Among
radiograph methods,it is most sensitive to changes in bone mass;
however it is less precise, is more costly and results in a
higher exposure to radiation than dual-energy absorptiometry.15
DEXA
( Dual energy x-ray absorptiometry) has a high rate of
precision and subjects the patients to an extremy low dose of
radiation.It currently the most frequently used method of
evaluating bone density in clinical practice.
Bone
Biopsy: Tetracycline labeling of the skeleton allows
determination of the rate of remodeling as well as evaluation
for other metabolic bone diseases. The current use of BMD test,
in combination with hormonal evaluation and biochemical markers
of bone remodeling, has largely replaced bone biopsy.
Treatment:
Non-pharmacological
prevention of osteoporosis:
Nutrition:
The role of calcium in attaining an adequate peak bone mass and
reducing age-related bone loss has been thoroughly investigated.
In spite of all published data there is no universal agreement
as to the required daily intake of calcium. In 1994 a consensus
conference recommended a daily intake of 1200 to 1500 per day,
1000 mg. for adults up to 65 year and 1500 mg. for
post-menopausal woman.16 Absorption of calcium is dependent on
the level of vit-D.
Physical
Activity: The frequency of falls is the most potent risk for
fractures. A recent prospective RCTs have shown that exercise
can reduce the risk of falling in elderly.17, 18
Bone responds to exercise less in adulthood than during growth.
In the adult and after the menopause, physical activity should
be regarded as bone-preserving rather than bone building.
Several studies and RCTs have shown that exercise increases the
BMD by few percentage points at best.19, 20
Hip
protectors: Energy absorption in the soft tissue around
the hip has been shown to protect against fractures of the hip.
Partly explaining why the overweight has fewer such injuries.21
Pharmological
prevention of osteoporotic fractures:
Calcium and vit-D- Calcium supplement, generally in a dose of
500 mg to 1000 mg. daily is known to slow the rate of loss of
BMD in elderly patients with a low calcium intake.22, 23 Calcium
in conjunction with vit-D has been shown to reduce the incidence
of hip fracture in elderly dwellers in nursing home.
An RCT carried out in France included women living in care homes
who were treated daily for three years with 1200mg of calcium
and 800 IU of vit-D. They had a reduction in fractures of the
hip of 29% and fewer non-vertebral fracture 24% compared with
placebo group.24, 25
One recent meta-analysis included showed that vit-D did not
reduce the risk of fractures, but in combination of calcium, the
risk was reduced by 26% in elderly patients living in care
home.26
Hormone
replacement therapy:
Several small RCTs have supported the view that estrogen
increases the BMD over a period of one to three years by a few
percentage points and reduced the risk of fracture in the spine
by about 50%. 27
One meta-analysis: showed that reduction of 33% in vertebral
fracture by HRT.
However
HRT has many serious adverse effects, including vaginal
bleeding, breast tenderness, deep vein thrombosis and pulmonary
embolism, stroke, heart disease and gall bladder disease and
increased risk of breast endometrial and ovarian cancer after
long-term use. 28 On this basis estrogen is not recommended
currently as the primary prevention of osteoporosis in most
countries.
Selective
estrogen receptor modulator (SERM)
A selective receptor modulator (SERM) such as raloxifene is an
antagonist of estrogen in the breast and the endometrium but an
agonist in bone and lipid metabolism. Raloxifene also lowers the
frequency of breast cancer by 70% 29 but increase the incidence
of venous thrombosis and pulmonary embolism at a similar rate as
HRT.30
As new SERMs are under development in phase III trails their
numbers will probably expend in the future.
Bisphonates:
A recent meta- analysis with use of Etidronate showed that
reduction of vertebral fractures by 40%. Whereas no effect on
other fractures.31
Alendranate is another bisphonate in which RCTs have shown a
reduction in hip Fractures by 51% and vertebral fracture 47% as
compared with placebo treatment. The dose was 5 mg daily for 2
years followed by 10 mg daily in third years.32
A recent metaanalysis showed that daily use of 10 mg of
alendronate, which reduce the vertebral fracture by 48% and non-
vertebral fractures by 49%. 33 Metaanalysis with Reserdronate
showed that reduces the vertebral fractures by 36% and non
–vertebral fractures by 27%. 34
Calcitonin:
A recent metaanalysis evaluating calcitonin showed reduces the
incidence of vertebral fractures by 54%. 35 The daily 200 IU of
intranasal salmon calcitonin/day reduce the risk of vertebral
fractures by 31% but no effect on peripheral fractures.36
Parathyroid Hormone:Intermittent
injection of PTH in individuals with osteoporosis stimulates the
formation of bones, increases the BMD and reduces the risk of
fractures.37
Strontium-
A recent RCTs suggested that 2 mg of strontium /day over 3 years
reduces the risk of sustaing a new vertebral fractures by 49%
during the first year and by 41% during the entire period.38
Other
Drugs- Fluoride is incorporated into the hydroxyapetite crystal
of bone. It stimulates recruitment and activity of osteoblast
increases the BMD in spine and to a less extent in the hip.39
Alphacalcidol and calcitrol are vit-D analogues, which have been
shown to increase the BMD.40 Menatetrenone, a vit-K2 compound,
has been shown to omprove theBMD.41
The Role of
Orthopaedic Surgeon
Orthopaedics
surgeon sees many patients with osteoporosis. It is silent
disease without any preceding symptoms until the first fractures
occur. Evaluation of patients must therefore include a history
of risk factors and BMD scan. It is the responsibility of the
Orthopaedics surgeon to arrange for patients to be properly
adviced and investigated for osteoporosis.
Synopsis of Major
Recommendations To The Physician
*
Counsel all women on the risk of osteoporosis and related
fractures.
* Advise
all patients to consume adequate amounts of calcium (at least
1200 mg /day, including supplements if necessary)
and vit-D (400 to 800 IU /day for individuals at risk of
deficiency)
*
Recommended regular weight – bearing and muscles
–strengthening exercise to reduce the risk of falls and
fractures.
* Advice
patients to avoid tobacco smoking and excessive alcohol intake.
*
Recommend BMD testing to all women aged 65 and older.
*
Recommended BMD testing to postmenopausal women who have
suffered a fragility fracture to conform the diagnosis and
determine disease severity.
*
Initiate therapy to reduce fracture risk in postmenopausal women
with BMD T- scores by central dual X-ray absorptiometry (DXA)
below –2 in the absence of risk factors and in women with T-
scores below –1.5 if one or more risk factors is present.
* Consider postmenopausal
women with vertebral or hip fractures candidates for
osteoporosis treatment.
Reference :
- Heaney, R.P: Calcium intake and bone health. In Postmenopausal
Osteoporosis: Prevention and Treatment, edited by
P.Coissac.Davos
,
Switzerland
, Sandoz, 1985
- Heaney, R.P: Calcium, bone health and osteoporosis. In Bone and Minerral
Reserch/4,edited by W.A Peck.Ed.4, pp.255-301.Amsterdam,
Elsevier, 1986
- Heany,
R.P.; Recker, R.R.; and Saville, P.D.: Calcium balance and
calcium requirements in middle-aged
women.Am.J.Clin.Nutr.,30:1603-1611,1977
- Heany,
R.P.; Recker, R.R.; and Saville, P.D.: Menopausal changes in
calcium balance performance.J.Lab.and Clin.Med.92953-963, 1978.
- Cummings’s, Kelsey, J.L, Nevitt, M.C, et al. Epidemiology of
osteoporosis and osteoporotic fractures. Epidemiol. Rev.,
7:178-208,1985
- Riggs, B.L, Melton, L.J III.Evidence for two distinct syndromes of
involutional osteoporosis.Am.J.Med.75: 899-901,1983.
- Lane, J.M.Healy, J.H. (editors): Diagnosis and Management of
pathological fractures.
New York
, Raven press, 1993.
- Austin
, L.A, Health, H., III: Calcitonin: physiology and
Pathophysiology.New England J.Med.304: 269-278,1981
- Cann,
C.E.; Cavanaugh, D.J.; Schnurfield, K et al. Menstrual history
is the primary determinant of trabecular bone density in women
runners (abstract). Med. and Sci.Sports and Exerc. 20
(Supplementum): 559,1998
- Warren
, M.P.; Fox, R.P.; DeRogatis, A.J. Osteopenia in hypothalamic
amenorrhea: a 3 years longitudinal study (abstract). Endocrine
Soc.Ann.Meet. 76: 461,1994
- Hahn, T.J.: Steroid and drug
induced osteopenia. In Primer on the Metabolic Bone disease and
Disorders of Mineral Metabolism, edited by M.J.Favus.Ed.2,
pp.250-255.New
York
, Raven Press, 1993.
- Mosekilde, L,; Erickson
,E.F,Charles, P : Effects of thyroid hormones on bone and
mineral metabolism.Endocrinolol. and Metab. Clin.North
America
, 19:35-63,1990.
- Hui, S.L; Slemenda, C.W:
Baseline measurement of bone mass predicts fracture in white
women. Ann. Intern. Med., 111:355-361,1989
- Kelly, T.L; Crane, G, Baran,
D.T. Single X-ray absorptiometry of the forearm: precision,
correlation, and reference data. Calci.Tissue Internat.
54:212-218,1994
- Schneider, R, math, K.: Bone density
Analysis, an update.Curr.Opin.Orthop.5 (5): 66-72,1994
- No author listed. NIH consensus
development panel on optimal calcium intake. JAMA 1994;
272-1942-8
- Province MA, Hadley EC, Hernbrook MC ET AL. The effects of exercise on falls in elderly
patients: a preplanned meta-analysis of the RCSIT trials. JAMA
1995:273:1341-7.
- Wolf SL, Barnhart HX, Ellison
GL, Coogler CE. The effect of Tai Chi Quan and computerized
balance training on postural stability in older subjects. Phys
Ther 1997:77; 371-81.
- Reinonne A, Oja P, Sievanen H,
Pasanen M et al. Effect of two training regimens on bone mineral
density in healthy perimenopausal women: a randomized control
trial.j.Bone Miner Res 1998:13:483-90
- Heinonen A, Kannus P, Sievanen H
et al. Randomized controlled trial of effect of high impact
exercise on selected risk factors for osteoporotic fractures.
Lancet 1996:348:1343-7
- Laurltzen JB, Jansen P, Peterson
MM et al. Body fat distribution and hip fractures. Acta Orthop
Scand 1992; 63:89
- Cummings SR, Black DM, Nevitt MC
et al Bone density at various sites for prediction of hip
fractures. Lancet 1993:341:72-57
- Cummings SR, Nevitt MC, Browner
WS et al. Risk factors for hip fracture in white women .N Engl J
Med 1995; 332:767-73
- Chapuy MC, Arlot ME, Delmas KM
ET al. Effect of calcium and cholecalciferol treatment for three
years on hip fractures in elderly women. BMJ 1994; 308:1081-2
- Chapuy MC, Arlot ME,
Duboeuf F et al. Vitamin D3 and calcium to prevent hip fractures
in elderly women.N.Engl J Med 1992; 327:1637-42
- Gillespie WJ, Avenell A, Henry
DA et al. Vitamin D and vitamin D analogies for preventing
fractures associated with involutional and post-menopausal
osteoporosis. Cochrane Database Syst Rev 2001:00000227
- Lufkin EG, Wahner HW, O
Fallon WM: Treatment of postmenopausal osteoporosis with
transdermal estrogen. Ann intern Med. 1992; 117:1-9
- Rossouw JE, Anderson GL,
Prentice RL et al. Risk and benefits of estrogen plus progestin
in healthy postmenopausal women principal results from the
women’s health initiative randomized controlled trial. JAMA
2002; 288:321-33
- Cauley JA, Norton L, Lippmann ME
et al. Continued breast cancer risk reduction in postmenopausal
women treated with raloxifen: 4 years results from the MORE
trial: Breast cancer Res. Treat 2001; 65:125-34
- Barrett- Connor E, Grady D, Sashegyi A: Raloxifene and cardiovascular events in osteoporotic
postmenopausal women four year results from the MORE (Multiple
Outcomes of Raloxifene Evaluation randomized trial. JAMA 2002;
287:847-57
- Cranney A, Guyatt G, Krollcki N
et al. A meta-analysis of etidronate for the treatment of
postmenopausal osteoporosis. Osteoporosis Int.2001; 12-140-51
- Hosking D, Chilvers CE,
Christiansen C et al. Prevention of bone loss with alendronate
in postmenopausal women under 60 years of age. N Eng J Med 1998;
338:485-92
- Cranney A, Wells G, Willan A et
al.
Meta
-analysis of therapies for postmenopausal osteoporosis .II:
metaanalysis of alendronate for the treatment of postmenopausal
women. Endocr Rev 2002; 23:508-16
- Cranney A, Tugwell P, Adachi J
et al. Meta-analysis of therapies for postmenopausal
osteoporosis.III.meta-analysis of resedronate for the treatment
of postmenopausal osteoporosis. Endocr Rev 2002; 23:517-23
- Cranney A, Tugwell P, Zytaruk N
et al. Meta-analysis of therapies for postmenopausal
osteoporosis.VI.meta-analysis of calcitonin for the treatment of
postmenopausal osteoporosis. Endocr Rev 2002; 23:540 -51
- Chestnut CH 3 rd, Silverman S, Andriano K et al. A randomized trial of nasal spray salmon
calcitonin in postmenopausal women with established
osteoporosis: the prevention of osteoporotic fractures study. Am
J Med. 2000; 109:267-76
- Seeman E, Delms PD.
Reconstructing the skeleton with intermittent parathyroid
hormone. Trends Endocrinol Metab 2001; 12:281-3
- Meunier PJ, Roux C, Seeman E et
al. The effect of strontium ranelate on the risk of vertebral
fracture in women with postmenopausal osteoporosis. N Engl J
Med. 2004; 350:459-68
- Meunier PJ, Sebert JL, Reginster
JY et al. Fluoride salts are no better at preventing new
vertebral fractures than calcium-vitamin D in postmenopausal
osteoporosis: the FAVO study. Osteoporosis Int 1998;B, 4-12
- Gallagher JC, Goldgar
D.Treatment of Postmenopausal osteoporosis with high dose of
synthetic calcitriol: a randomized controlled study. Ann Intern
Med 1990:113:649-55
- Iwanamoto I, Kusha S, Noguchi S
et al .A longitudinal study of the effect of vitamin K2 on bone
mineral density in postmenopausal women: a comparative study
with vitamin D3 and estrogen-progestin therapy. Matruritas 1999;
31:164-4
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