Osteoporosis Tutorial for Medical Education

Osteoporosis Tutorial for medical education - WebPath

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Osteoporosis

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General FeaturesOsteoporosis is accelerated bone loss. Normally, there is loss of bone mass with aging, perhaps0.7% per year in adults. However, bone loss is greater in women past menopause than in menof the same age. The process of bone remodeling from resorption to matrix synthesis tomineralization normally takes about 8 months--a slow but constant process. Bone in olderpersons just isn't as efficient as bone in younger persons at maintaining itself--there is decreasedactivity of osteoblasts and decreased production of growth factors and bone matrix. (Sambrookand 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 womanwho begins with diminished bone density (B) even before menopause is at great risk, particularlywith a more accelerated rate of bone loss. Interventions such as postmenopausal estrogen (withprogesterone) therapy, the use of drugs such as the non-hormonal compound alendronate thatdiminishes osteoclast activity, and the use of diet and exercise regimens can help to slow boneloss (C) but will not stop bone loss completely or restore prior bone density. Diet and exercisehave a great benefit in younger women to help build up bone density and provide a greaterreserve against bone loss with aging. (Winslow et al, 2009)

The World Health Organization (WHO) has defined osteoporosis as a spinal or hip bone mineraldensity (BMD) that is 2.5 standard deviations or more below the mean BMD for healthy, youngwomen, measured by dual energy x-ray absorptiometry (DEXA). The WHO defines osteopeniaas 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



Bone MetabolismBone 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 factorkappa-B ligand (RANKL). Hematopoietic cell precursors stimulated by M-CSF give rise toosteoclasts that express RANK receptor. The RANKL/RANK interaction stimulates differentationof the osteoclasts so that they can resorb bone. Osteoblasts also produce a decoy receptorcalled osteoprotegerin (OPG) that binds to RANKL and prevents the RANKL/RANK interaction.

Estradiol increases production of OPG to diminish bone resorption. Glucocorticoids stimulateRANKL expression while inhibiting OPG synthesis by osteoblasts to enhance osteoclastproliferation 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. Inaddition, osteocyte apoptosis is enhanced to reduce bone strength even before there is markedloss of bone mineral density. (Weinstein, 2011)



Risk FactorsRisk 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 formseen in older persons and women past menopause in which bone loss is accelerated over thatpredicted for age and sex. Secondary osteoporosis results from a variety of identifiableconditions 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)



DiagnosisDiagnosis 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 areavailable, including single-photon absorptiometry, dual-photon absorptiometry, quantitativecomputed tomography (QCT), dual x-ray absorptiometry (DEXA), and ultrasonography. Mostoften, site specific measurements are performed. The most common sites analyzed are thosewith greatest risk for fracture: hip, wrist, and vertebrae. The forearm and heel are more easilymeasured using single-photon absorptiometry, quantitative computed tomography, andquantitative ultrasonography, but these sites are typically unresponsive to therapy and give lessinformation about response to therapy. Hip (femur) and vertebra can be easily measured byDEXA with an instrument dedicated to this task.

A graphical display of a DEXA scan for the hip (femur) is shown below, comparing bone mineraldensity (BMD) to age and T-score (in standard deviations above or below the comparablehealthy young adult woman's mean BMD). The asterisk representing a woman at age 48 iswithin the expected range for age. The circle marks the BMD for a woman age 60 and isconcerning for greater bone loss from osteopenia (-1 to -2.5) but not yet osteoporosis. The Xmarks the BMD for a woman age 76 and is in the range of osteoporosis (> -2.5) with increasedrisk for fracture.



Increased risk for fracture correlates with decreasing bone density. Serial measurements overtime 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 serumand deoxypyridinoline and pyridinoline in urine. (Bonnick and Shulman, 2006)

Alkaline phosphatase, which reflects osteoclast activity in bone, lacks sensitivity andspecificity for osteoporosis, because it can be elevated or decreased with many diseases.It is increased with aging. Fractionating alkaline phosphatase for the fraction more specificto bone doesn't increase usefulness that much.

Osteocalcin, also known as bone gamma-carboxyglutamate. It is synthesized byosteoblasts and incorporated into the extracellular matrix of bone, but a small amount isreleased into the circulation, where it can be measured in serum. The levels of circulatingosteocalcin correlate with bone mineralization, but are influenced by age, sex, andseasonal variation. Laboratory methods also vary.

The bone resorption markers in urine are breakdown products of type I collagen andinclude pyridinium crosslinks known as pyridinoline and deoxypyridinoline. They reflectbone remodeling but not the status of bone mineral density.



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

Consequences of OsteoporosisOsteoporotic bone is histologically normal in its composition--there is just less bone. This resultsin weakened bones that are more prone to fractures with trauma, even minor trauma. The areasmost 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 toa wheelchair. It is also possible to surgically put in a prosthetic hip joint. Wrist fractures arecommon 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 fracturesmay result in back pain. Another consequence is shortening or kyphosis (bending over) of thespine. 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 fromthe complications that come from hospitalization with immobilization, such as pulmonarythromboembolism and pneumonia.

Osteoporosis is so common that, on average, about 1 in 2 elderly Caucasian women will havehad a fracture. In contrast, only about 1 in 40 men of similar age will have had a fracture. Menstart 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. Normal vertebral bone, gross.2. Normal vertebral bone, gross.3. Normal vertebral bone and marrow, low power microscopic.4. Normal vertebral bone, polarized, medium power microscopic.5. Vertebral bone with osteoporosis, gross.6. Vertebral bone with osteoporosis and compressed fracture, gross.7. Vertebral bone with osteoporosis, low power microscopic.8. Femur with osteoporosis, radiograph.



9. Femoral neck fracture, radiographs.10. Hip prosthesis, radiograph.

Prevention StrategiesThe 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 andmaintain bone mass. This will provide a good reserve against bone loss later in life. Exerciseplaces stress on bones that builds up bone mass, particularly skeletal loading from musclecontraction with weight training exercises. However, any exercise of any type is better thannone at all, and exercise also provides benefits for prevention of cardiovascular diseases thatare 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, aswell as dairr products. Appropriate protein intake has an anabolic effect to build osteoid matrix.(Tucker, 2009)

TreatmentPersons with osteoporosis may benefit from an improved diet, including supplementation withvitamin 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 thathas been resorbed but not replaced, and this accounts for about 5 to 10% of bone mass. Bydecreasing resorbtion of bone, a gain in bone density of 5 to 10% is possible, taking about 2 to3 years. However, no drug therapy will restore bone mass to normal. Women past menopausewith accelerated bone loss may benefit from hormonal therapy using estrogen withprogesterone. The estrogen retards bone resorption and thus diminishes bone loss. This effectis most prominent in the first years after menopause, while risks from hormone replacementtherapy increase. (Nelson et al, 2002)

One of the more common non-estrogen therapies is the use of bisphosphonates such asalendronate or risedronate that act an an inhibitor of osteoclastic activity. Bisphosphonates maybe beneficial, particularly in women who cannot tolerate estrogen therapy. Bisphosphonaes areeffective in inhibiting bone loss after menopause. In one study risedronate has showneffectiveness in reducing the risk of hip fracture among elderly women with osteoporosis. Shortterm adverse effects of bisphosphonate therapy include esophagitis, musculoskeletal pain,ocular inflammation, and hypocalcemia. Long term adverse effects include increased risk for



esophageal cancer, osteonecrosis of the jaw, femoral fracture, and atrial fibrillation. (Kennel andDrake, 2009)

Raloxifene is a selective estrogen receptor modulator (SERM) that may also replace estrogentherapy. Raloxifene can act in concert with estrogen in bone to inhibit resorbtion and decreasethe risk for fractures. Though raloxifene inhibits bone resorbtion, it does not have an anaboliceffect. Additional potential benefits from raloxifene therapy include decreased risk for breastcancer, 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 subcutaneousinjection which binds to specific high-affinity cell-surface receptors in bone and kidney, similar tothe 34 N-terminal amino acids of parathyroid hormone, and has the same physiological actionson bone and kidney. Daily administration of teriparatide stimulates new bone formation bypromoting osteoblastic activity over osteoclastic activity, improving trabecular bone architecturalremodelling 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 ofnuclear factor-kappaB ligand (RANKL) that is elaborated by osteoblasts. The RANKL interactingwith RANK receptor expressed on osteoclasts is affected by this drug, leading to reducedosteoclast activation and survival, thus inhibiting bone resorbtion that helps increase bonemineral 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 boneresorbtion, may be taken by injection or by nasal spray. Sodium fluoride can increase themeasured bone density in vertebra, but seems to have no overall effectiveness in reducingvertebral fracture. Zoledronic acid has shown effectiveness in treating bone loss. (Rahmani andMorin, 2009)

ReferencesBinkley 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, boneturnover 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.



2007;99:350-356.

Kennel KA, Drake MT. Adverse effects of bisphosphonates: implications for osteoporosismanagement. 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 postmenopausalosteoporosis. Drugs Aging. 2011;28(1):63-82.

Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormonereplacement therapy: scientific review. JAMA. 2002;288:872-881.

Rahmani P, Morin S. Prevention of osteoporosis-related fractures among postmenopausalwomen 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 ofosteoporosis. 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 ofnuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications. J ClinEndocrinol 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 thepathogenesis of osteoporosis. Curr Osteoporos Rep. 2009;7:140-144.

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Osteoporosis Tutorial for Medical Education