Osteoporosis Tutorial for medical education - WebPath

Osteoporosis
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General Features
Osteoporosis is accelerated bone loss. Normally, there is loss of bone mass with aging, perhaps
0.7% per year in adults. However, bone loss is greater in women past menopause than in men
of the same age. The process of bone remodeling from resorption to matrix synthesis to
mineralization normally takes about 8 months--a slow but constant process. Bone in older
persons just isn't as efficient as bone in younger persons at maintaining itself--there is decreased
activity of osteoblasts and decreased production of growth factors and bone matrix. (Sambrook
and Cooper, 2006)

This diagram illustrates changes in bone density with aging in women. The normal curve (A)
steepens following menopause, but even by old age the risk for fracture is still low. A woman
who begins with diminished bone density (B) even before menopause is at great risk, particularly
with a more accelerated rate of bone loss. Interventions such as postmenopausal estrogen (with
progesterone) therapy, the use of drugs such as the non-hormonal compound alendronate that
diminishes osteoclast activity, and the use of diet and exercise regimens can help to slow bone
loss (C) but will not stop bone loss completely or restore prior bone density. Diet and exercise
have a great benefit in younger women to help build up bone density and provide a greater
reserve against bone loss with aging. (Winslow et al, 2009)
The World Health Organization (WHO) has defined osteoporosis as a spinal or hip bone mineral
density (BMD) that is 2.5 standard deviations or more below the mean BMD for healthy, young
women, measured by dual energy x-ray absorptiometry (DEXA). The WHO defines osteopenia
as a spinal or hip BMD between 1 and 2.5 standard deviations below the mean for healthy,
young women. (Sweet et al, 2009)
Fracture risk can be estimated at: http://osteoed.org/tools.php

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Bone Metabolism
Bone metabolism is controlled by a variety of factors.

Parathyroid hormone receptors are found on osteoblasts. Parathyroid hormone (PTH)

stimulation of osteoblasts increases osteoblast production of receptor activator of nuclear factor
kappa-B ligand (RANKL). Hematopoietic cell precursors stimulated by M-CSF give rise to
osteoclasts that express RANK receptor. The RANKL/RANK interaction stimulates differentation
of the osteoclasts so that they can resorb bone. Osteoblasts also produce a decoy receptor
called osteoprotegerin (OPG) that binds to RANKL and prevents the RANKL/RANK interaction.
Estradiol increases production of OPG to diminish bone resorption. Glucocorticoids stimulate
RANKL expression while inhibiting OPG synthesis by osteoblasts to enhance osteoclast
proliferation and differentiation, leading to bone resorption. (Vega et al, 2007) (Romas, 2009)
Prolonged corticosteroid therapy leads to a reduction in osteoblasts and osteoclasts. However,
there is prolonged survival of osteoclasts, leading to an imbalance with net bone loss. In
addition, osteocyte apoptosis is enhanced to reduce bone strength even before there is marked
loss of bone mineral density. (Weinstein, 2011)

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Risk Factors
Risk factors for osteoporosis include:
Female sex
Age > 70 years
Caucasian or Asian race
Early onset of menopause
Longer postmenopausal interval
Inactivity, especially lack of weight bearing exercise
Osteoporosis can be classified as primary or secondary. Primary osteoporosis is simply the form
seen in older persons and women past menopause in which bone loss is accelerated over that
predicted for age and sex. Secondary osteoporosis results from a variety of identifiable
conditions that may include: (Sweet et al, 2009)
Metabolic bone disease, such as hyperparathyroidism
Neoplasia, as with multiple myeloma or metastatic carcinoma
Malnutrition
Drug therapy, as with corticosteroids
Prolonged immobilization
Weightlessness with space travel
Modifiable risk factors that may potentiate osteoporosis include:
1. Smoking
2. Alcohol abuse
3. Excessive caffeine consumption
4. Excessive dietary protein consumption
5. Lack of dietary calcium
6. Lack of sunlight exposure (to generate endogenous vitamin D)

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Diagnosis
Diagnosis of osteoporosis is made by three methods:
1. Radiographic measurement of bone density
2. Laboratory biochemical markers
3. Bone with pathologic assessment
Of these three the best is radiographic bone density measurement. A variety of techniques are
available, including single-photon absorptiometry, dual-photon absorptiometry, quantitative
computed tomography (QCT), dual x-ray absorptiometry (DEXA), and ultrasonography. Most
often, site specific measurements are performed. The most common sites analyzed are those
with greatest risk for fracture: hip, wrist, and vertebrae. The forearm and heel are more easily
measured using single-photon absorptiometry, quantitative computed tomography, and
quantitative ultrasonography, but these sites are typically unresponsive to therapy and give less
information about response to therapy. Hip (femur) and vertebra can be easily measured by
DEXA with an instrument dedicated to this task.
A graphical display of a DEXA scan for the hip (femur) is shown below, comparing bone mineral
density (BMD) to age and T-score (in standard deviations above or below the comparable
healthy young adult woman's mean BMD). The asterisk representing a woman at age 48 is
within the expected range for age. The circle marks the BMD for a woman age 60 and is
concerning for greater bone loss from osteopenia (-1 to -2.5) but not yet osteoporosis. The X
marks the BMD for a woman age 76 and is in the range of osteoporosis (> -2.5) with increased
risk for fracture.

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Increased risk for fracture correlates with decreasing bone density. Serial measurements over
time can also give an indication of the rate of bone loss and prognosis (Bonnick and Shulman,
2006) (El Maghraoui and Roux, 2008).
Biochemical markers for bone turnover include bone alkaline phosphatase, osteocalcin in serum
and deoxypyridinoline and pyridinoline in urine. (Bonnick and Shulman, 2006)
Alkaline phosphatase, which reflects osteoclast activity in bone, lacks sensitivity and
specificity for osteoporosis, because it can be elevated or decreased with many diseases.
It is increased with aging. Fractionating alkaline phosphatase for the fraction more specific
to bone doesn't increase usefulness that much.
Osteocalcin, also known as bone gamma-carboxyglutamate. It is synthesized by
osteoblasts and incorporated into the extracellular matrix of bone, but a small amount is
released into the circulation, where it can be measured in serum. The levels of circulating
osteocalcin correlate with bone mineralization, but are influenced by age, sex, and
seasonal variation. Laboratory methods also vary.
The bone resorption markers in urine are breakdown products of type I collagen and
include pyridinium crosslinks known as pyridinoline and deoxypyridinoline. They reflect
bone remodeling but not the status of bone mineral density.

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Bone biopsy is not often utilized for assessment of bone density. This test has limited
availability, and is most often performed as a research technique for analysis of treatment
regimens for bone diseases. Bone biopsy involves double tetracycline labelling to determine
appositional bone growth. Doses of tetracycline are given weeks apart, and the bone biopsy is
embedded in a plastic compound, sliced thinly, and examined under fluorescent light, where the
lines of tetracycline (which autofluoresce) will appear and appositional growth assessed.
Osteomalacia, for example, has diminished appositional growth. (Malluche et al, 2007)

Consequences of Osteoporosis
Osteoporotic bone is histologically normal in its composition--there is just less bone. This results
in weakened bones that are more prone to fractures with trauma, even minor trauma. The areas
most affected are:
Hip (femoral head and neck)
Wrist
Vertebrae
Hip fractures that occur, even with minor falls, can be disabling and confine an elderly person to
a wheelchair. It is also possible to surgically put in a prosthetic hip joint. Wrist fractures are
common with falls forward with arms extended to break the fall, but the wrist bones break too.
Vertebral fractures are of the compressed variety and may be more subtle. Vertebral fractures
may result in back pain. Another consequence is shortening or kyphosis (bending over) of the
spine. This can lead to the appearance of a "hunched over" appearance that, if severe enough,
can even compromise respiratory function because the thorax is reduced in size.
Persons suffering fractures are at greater risk for death, not directly from the fracture, but from
the complications that come from hospitalization with immobilization, such as pulmonary
thromboembolism and pneumonia.
Osteoporosis is so common that, on average, about 1 in 2 elderly Caucasian women will have
had a fracture. In contrast, only about 1 in 40 men of similar age will have had a fracture. Men
start out with a greater bone mass to begin with, so they have a greater reserve against loss.
However, that is still a large number of men with osteoporosis. (Binkley, 2009)
1.
2.
3.
4.
5.
6.
7.
8.

Normal vertebral bone, gross.

Normal vertebral bone, gross.
Normal vertebral bone and marrow, low power microscopic.
Normal vertebral bone, polarized, medium power microscopic.
Vertebral bone with osteoporosis, gross.
Vertebral bone with osteoporosis and compressed fracture, gross.
Vertebral bone with osteoporosis, low power microscopic.
Femur with osteoporosis, radiograph.

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9. Femoral neck fracture, radiographs.

10. Hip prosthesis, radiograph.

Prevention Strategies
The best long-term approach to osteoporosis is prevention. If children and young adults,
particularly women, have a good diet and get plenty of exercise, then they will build up and
maintain bone mass. This will provide a good reserve against bone loss later in life. Exercise
places stress on bones that builds up bone mass, particularly skeletal loading from muscle
contraction with weight training exercises. However, any exercise of any type is better than
none at all, and exercise also provides benefits for prevention of cardiovascular diseases that
are more common in the elderly. Athletes tend to have greater bone mass than non-athletes.
Exercise in later life will help to retard the rate of bone loss. (Sweet et al, 2009)
A healthy diet should include not only enough calcium and vitamin D, but also other nutrients,
including a range of vitamins and minerals found in a diet that contains fruit and vegetables, as
well as dairr products. Appropriate protein intake has an anabolic effect to build osteoid matrix.
(Tucker, 2009)

Treatment
Persons with osteoporosis may benefit from an improved diet, including supplementation with
vitamin D and calcium, and moderate exercise to help slow further bone loss.
Most drug therapies work by decreasing bone resorbtion. At any given time, there is bone that
has been resorbed but not replaced, and this accounts for about 5 to 10% of bone mass. By
decreasing resorbtion of bone, a gain in bone density of 5 to 10% is possible, taking about 2 to
3 years. However, no drug therapy will restore bone mass to normal. Women past menopause
with accelerated bone loss may benefit from hormonal therapy using estrogen with
progesterone. The estrogen retards bone resorption and thus diminishes bone loss. This effect
is most prominent in the first years after menopause, while risks from hormone replacement
therapy increase. (Nelson et al, 2002)
One of the more common non-estrogen therapies is the use of bisphosphonates such as
alendronate or risedronate that act an an inhibitor of osteoclastic activity. Bisphosphonates may
be beneficial, particularly in women who cannot tolerate estrogen therapy. Bisphosphonaes are
effective in inhibiting bone loss after menopause. In one study risedronate has shown
effectiveness in reducing the risk of hip fracture among elderly women with osteoporosis. Short
term adverse effects of bisphosphonate therapy include esophagitis, musculoskeletal pain,
ocular inflammation, and hypocalcemia. Long term adverse effects include increased risk for

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esophageal cancer, osteonecrosis of the jaw, femoral fracture, and atrial fibrillation. (Kennel and
Drake, 2009)
Raloxifene is a selective estrogen receptor modulator (SERM) that may also replace estrogen
therapy. Raloxifene can act in concert with estrogen in bone to inhibit resorbtion and decrease
the risk for fractures. Though raloxifene inhibits bone resorbtion, it does not have an anabolic
effect. Additional potential benefits from raloxifene therapy include decreased risk for breast
cancer, because raloxifene acts antagonistically to estrogen on the uterus. Conversely,
raloxifene acts in concert with estrogen to protect against and reduce atherogenesis. (Jordan,
2007)
Teriparatide is a recombinant human parathyroid hormone administered by subcutaneous
injection which binds to specific high-affinity cell-surface receptors in bone and kidney, similar to
the 34 N-terminal amino acids of parathyroid hormone, and has the same physiological actions
on bone and kidney. Daily administration of teriparatide stimulates new bone formation by
promoting osteoblastic activity over osteoclastic activity, improving trabecular bone architectural
remodelling and increasomg bone mass. (Cappuzzo and Delafuente, 2004) (Sweet et al, 2009)
Denosumab is a human monoclonal antibody that binds to and inhibits the receptor activator of
nuclear factor-kappaB ligand (RANKL) that is elaborated by osteoblasts. The RANKL interacting
with RANK receptor expressed on osteoclasts is affected by this drug, leading to reduced
osteoclast activation and survival, thus inhibiting bone resorbtion that helps increase bone
mineral density. Thus, densosumab mimics osteoprotegrin that is reduced in osteoporosis.
(Moen and Keam, 2011 )
Other drug therapies are less commonly employed. Calcitonin, a hormone that decreases bone
resorbtion, may be taken by injection or by nasal spray. Sodium fluoride can increase the
measured bone density in vertebra, but seems to have no overall effectiveness in reducing
vertebral fracture. Zoledronic acid has shown effectiveness in treating bone loss. (Rahmani and
Morin, 2009)

References
Binkley N. A perspective on male osteoporosis. Best Pract Res Clin Rheumatol.
2009;23:755-768.
Bonnick SL, Shulman L. Monitoring osteoporosis therapy: bone mineral density, bone
turnover markers, or both? Am J Med. 2006;119(4 Suppl 1):S25-31.
Cappuzzo KA, Delafuente JC. Teriparatide for severe osteoporosis. Ann Pharmacother.
2004;38(2):294-302.
El Maghraoui A, Roux C. DXA scanning in clinical practice. QJM. 2008;101:605-617.
Jordan VC. SERMs: meeting the promise of multifunctional medicines. J Natl Cancer Inst.

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Osteoporosis Tutorial for medical education - WebPath

2007;99:350-356.
Kennel KA, Drake MT. Adverse effects of bisphosphonates: implications for osteoporosis
management. Mayo Clin Proc. 2009;84:632-637.
Malluche HH, Mawad H, Monier-Faugere MC. Bone biopsy in patients with osteoporosis.
Curr Osteoporos Rep. 2007;5:146-152.
Moen MD, Keam SJ. Denosumab: a review of its use in the treatment of postmenopausal
osteoporosis. Drugs Aging. 2011;28(1):63-82.
Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone
replacement therapy: scientific review. JAMA. 2002;288:872-881.
Rahmani P, Morin S. Prevention of osteoporosis-related fractures among postmenopausal
women and older men. CMAJ. 2009;181:815-820.
Sambrook P, Cooper C. Osteoporosis. Lancet. 2006;367:2010-2018.
Sweet MG, Sweet JM, Jeremiah MP, Galazka SS. Diagnosis and treatment of
osteoporosis. Am Fam Physician. 2009;79:193-200.
Tucker KL. Osteoporosis prevention and nutrition. Curr Osteoporos Rep. 2009;7:111-117.
Vega D, Maalouf NM, Sakhaee K. CLINICAL Review #: the role of receptor activator of
nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications. J Clin
Endocrinol Metab. 2007;92:4514-4521.
Weinstein RS. Glucocorticoid-induced bone disease. N Engl J Med. 2011;365:62-70.
Winsloe C, Earl S, Dennison EM, Cooper C, Harvey NC. Early life factors in the
pathogenesis of osteoporosis. Curr Osteoporos Rep. 2009;7:140-144.

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