osteoporosis: epidemiology, histology, bone remodeling, and classification

Address all correspondence and request for reprints to:Peter A. HuijbregtsOlympic Physiotherapy and Hand Therapy#245-3066 Shelbourne StreetVictoria, BC V8R 6T9 [email protected]

Osteoporosis: Epidemiology, Histology, Bone Remodeling, andClassification

Abstract: Osteoporosis and decreased bone mineral density affect a large proportion of Americansof both sexes. Physical therapists play a role in screening for undiagnosed osteoporosis, and inprevention and treatment of osteoporosis. Bone mineral density is determined by the activity ofthe cells contained in bone. These cells react to demands on calcium and phosphate metabolism,hormonal influences, and mechanical loading. Osteoporosis can be classified as primary or sec-ondary.

Key Words: Osteoporosis, Epidemiology, Histology, Remodeling, Classification

Peter A. Huijbregts, DPT, OCS, FAAOMPT

D ecreased bone density or osteopenia is pathognomonic for osteoporosis1,2. Despite the decreased density,

the osteopenic bone in osteoporosis is normally miner-alized1-3. This distinguishes osteoporosis from osteoma-lacia, a condition with which it is commonly confused;in osteomalacia, the bone matrix is insufficiently miner-alized1,4. One way to assess bone mineral density (BMD)is by dual-energy X-ray absorptiometry (DEXA). Accord-ing to Glase and Kaplan1, the World Health Organization(WHO) has used this diagnostic test to establish criteriafor the classification of osteoporosis (Table 1). The physicaltherapist has three distinct roles with regards to patientsat risk for or diagnosed with osteoporosis or osteopenia. Our first role pertains to screening patients for os-teoporosis and osteopenia. The fracture threshold is a

hypothetical concept representing a BMD below whichfracture as a result of unspecified external forces becomesmore likely. Some physical therapy interventions maygenerate mechanical forces that exceed the fracture thresh-old in a patient with decreased BMD. In this era of directaccess to physical therapy services and limited patientcontact time with the primary-care physician due to managedcare constraints, the physical therapist, therefore, needsto be able to screen patients for a low BMD. Being ableto identify patients at risk for low BMD will not only allowthe therapist to appropriately choose intervention param-eters but also enable a timely referral to medical colleagues. Our other two roles deal with prevention and treat-ment. The Guide for Physical Therapist Practice5 con-tains a preferred practice pattern for primary preventionand risk-factor reduction for skeletal demineralization.It describes two treatment goals. One is having the pa-tient who is at risk for low BMD maintain a density abovethe fracture threshold. The other goal is having the patientwith identified low BMD reverse the demineralization processand achieve BMD above the fracture threshold. This article is Part I of a two-part series. The goal ofthis part is to increase the physical therapist’s knowl-

134 / The Journal of Manual & Manipulative Therapy, 2001The Journal of Manual & Manipulative TherapyVol. 9 No. 3 (2001), 134 - 142

edge of the epidemiology of osteoporosis, the histologyof bone, the influences on bone remodeling, and theclassification of osteoporosis. This knowledge will serveas a basis for the follow-up article, which deals with themore practical aspects of diagnosis and treatment. To-gether these two articles will enable the physical thera-pist to effectively screen patients for undiagnosed osteoporo-sis and to develop appropriate treatment programs forthose patients at risk for or diagnosed with osteoporosis.

Epidemiology Following the WHO classification mentioned aboveapproximately 0.6% of young women may be diagnosedwith osteoporosis; 16% are osteopenic. By age 75, some38% of white women are estimated to be osteoporotic,while 94% can be diagnosed with osteopenia1. Osteoporosisaffects between 20 and 25 million people in the UnitedStates3,6,7. This number has been estimated to increaseto 35 million by the year 20156. Reduced BMD decreases the mechanical strength ofbone and increases fracture risk1. Yearly 1.5 million fracturesare associated with osteoporosis: 700,000 vertebral frac-tures, 300,000 hip fractures, 250,000 distal forearm fractures,and another 250,000 fractures in other sites6. In 1995,the direct medical costs alone for treatment of osteoporoticfractures in the United States were estimated at 13.8 billiondollars8. Thirty percent of all white postmenopausal womeneventually have osteoporotic fractures3. Forty percent ofwomen in their eighties have fractured one or both hips9.Vertebral fractures occur in approximately 25% of post-menopausal women8. As cited by Kosmahl10, the NationalOsteoporosis Foundation estimated that 90% of these hipand vertebral fractures in older white women are to beattributed to osteoporosis. Osteoporosis is not limited to women: it affects anestimated 5 million men over the age of 50 in the UnitedStates. Approximately 5% of white, Asian, Hispanic, andNative American males aged 50-79 have osteoporosis; 3.5%of black men in this age group are osteoporotic. These

numbers increase to approximately 24% of white men,17% of black men, and 5% of Asian, Hispanic, and NativeAmerican men age group 80 and older. The lifetime riskof having an osteoporosis-related fracture for men over50 is estimated at 13%11. This may even be an underes-timation: Kelley et al11 quoted an Australian study thatfound a 29% residual lifetime risk for osteoporotic frac-tures in 60-year-old men of an average life expectancy.

Histology Bone tissue is the primary storage depot in the bodyfor calcium (Ca2+), phosphate (PO4

3-), sodium, and mag-nesium7. Bones contain the red (hematopoietic) marrow,where the blood cells are formed12. Bone protects com-ponents of the nervous system and visceral structures,provides a rigid internal support to the trunk and ex-tremities, and provides attachment sites for soft tissue,such as capsule, ligaments, and tendons3,12. It is a spe-cialized connective tissue composed of a cellular com-ponent, the organic bone matrix, and inorganic calcifiedintracellular material12. Internal and external surfaces ofbone are lined with the endosteum and periosteum, re-spectively12. The three main cell types in bone are osteoblasts,osteocytes, and osteoclasts12. Osteoblasts have an abun-dant endoplasmatic reticulum, characteristic of cellsmanufacturing proteins for export out of the cell13. Theyare formed by mitosis and differentiation of osteoprogenitorcells in the inner, more cellular layer of the periosteum,and in the endosteum which lines the internal surface ofbone cavities12. Osteoblasts are, therefore, only found atthe inner and outer surfaces of bone tissue. Due to theirlocation, resting osteoblasts are known as bone liningcells13. More metabolically active osteoblasts synthesizethe organic components of the bone matrix12. Depositionof the inorganic components of the bone matrix also dependson the presence of viable osteoblasts, presumably becauseof the ability of the osteoblasts to concentrate thesecomponents in intracytoplasmic vesicles which are re-

Group Diagnostic criteria

Normal BMD within 1 SD of the mean of a young adult reference population

Osteopenia BMD between 1.0 and 2.5 SD below the mean of a young adultreference population

Osteoporosis BMD greater or equal to 2.5 SD below the mean of a young adultreference population

Severe osteoporosis Osteoporosis with one or more fragility fractures

Table 1. World Health Organization diagnostic criteria for osteoporosis. BMD- bone mineral density; SD-standard deviation. Modified from Glase and Kaplan (1997)1

Osteoporosis: Epidemiology, Histology, BoneRemodeling, and Classification / 135

leased into the extracellular matrix when needed12. The osteoblasts produce a layer of initially uncalcifiedmatrix, called osteoid12. As this matrix is calcified, theosteoblasts, now called osteocytes, become contained withinthe matrix in lacunae12. There is one osteocyte per la-cuna. Osteocytes have a higher nucleus-to-cytoplasm ratiothan osteoblasts and contain less cell organelles13. Me-tabolites cannot diffuse through the calcified matrix:osteocytes extend cytoplasmic processes through thincylindrical spaces perforating the matrix, called canali-culi12. This way they form junctions with the cytoplas-mic processes of the osteocytes in adjacent lacunae, andeventually with blood vessels in order to perform theirfunction of maintaining the surrounding bone matrix12.The osteocytes are also in contact via these canaliculiwith the osteoblasts on the bone surface13. This fits intothe hypothesis that osteoblasts receive the majority oflocal and systemic signals and then transmit these to theother cells contained in bone13. Conversely, signals gen-erated due to mechanical deformation of the bone mightbe perceived in the local osteocytes, which could pass onregulatory information to the osteoblasts by way of thecanaliculi13. Osteoclasts are large motile, multinucleated cells12,13.Junqueira et al12 reported that they are formed by thefusion of blood-derived monocytes. Other authors havenoted that they are derived from the pluripotent cells ofbone marrow; these hematopoietic precursors also giverise to macrophages and monocytes13,14. Osteoclasts maymove from the bone marrow to the bone either by directmigration from the marrow, or by migration through thecirculation14, possibly explaining the controversy regardingtheir origin. Osteoclasts secrete hydrogen ions to facili-tate dissolution of calcium phosphate from the bone matrixas well as collagenase and other proteolytic enzymes tobreak down the organic bone matrix12. Osteoclasts do nothave receptors for a majority of the locally and systemi-cally released substances that affect bone cell function13

(we will discuss this later). For the osteoclast to resorbbone, the activated osteoblast must first contract some-what in order for the osteoclast to gain access to the bonesurface. The osteoblast must also produce and depositneutral proteases to degrade the thin layer of unmineralizedosteoid covering the bone. Osteoclasts may have to beexposed to a mineralized bone surface as well as certainmatrix components to become active13. Approximately 50-60% of the dry weight of the bonematrix is inorganic matter9,12. The main components arecalcium and phosporus, laid down alongside collagen fibers,both in the form of hydroxy-apatite crystals with thecomposition Ca10(PO4)6(OH)2, and as non-crystalline,amorphous calcium phosphate9,12. The surface ions of thehydroxy-apatite crystals are hydrated. This layer of wa-ter around the crystal, known as the hydration shell,facilitates rapid exchanges of ions between the crystaland the extracellular fluid12. The organic component of

the matrix consists of type I-collagen, proteoglycans,phosphoproteins, phospholipids, hyaluronic acid, andglycoproteins9. Several glycoproteins unique to bone tissuesuch as bone sialoprotein and osteocalcin have beenidentified; these proteins have a high affinity for calciumand may play a role in calcification of the bone matrix12.Also present in very small amounts in the bone matrixare growth factors and cytokines, such as transforminggrowth factor beta (TGF-beta), insulin-like growth fac-tor (IGF), interleukin (IL)-1 and IL-6, and bone morpho-genic proteins (BMP) 1 through 613. These substancesare capable of influencing bone cells; released from thematrix as a result of osteoclastic bone resorption, theymay play a role in a feedback mechanism that regulatesbone remodeling13. The two most common types of bone are compactbone and cancellous bone9,12. Visual observation of cross-sections of bone shows dense areas without any cavities,corresponding with compact bone, and areas with mul-tiple interconnecting cavities, corresponding with can-cellous bone. Because of its structure, cancellous boneis also known as spongy or trabecular bone9,12. Compactbone is located in the cortex of bones and in the shaft(diaphysis) of the long bones: it is, therefore, also knownas cortical bone9. Cancellous bone is found in the bul-bous ends or epiphyses of the long bones, covered by athin layer of compact bone; in a thin layer underneaththicker compact bone lining the marrow cavity of thelong bones; and in the core of the short bones12. Themicroscopic structure of compact bone and of the bonein the trabeculae separating the cavities in cancellousbone is similar despite the distinctly different appearanceon gross observation12. Compact and cancellous boneinvolvement is used to differentiate between the differ-ent types of osteoporosis3,9.

Bone Remodeling During life, bone is constantly being resorbed andnewly formed: the turnover rate of calcium in bone is100% per year in infants and 18% per year in adults15.Bone turnover is a surface event; because cancellous bonehas a greater surface area than compact bone, its turn-over is more rapid13. The renewal rate is about 4% peryear for compact bone versus 20% for cancellous bone15.The three primary influences on the bone remodelingprocess7 are discussed next:

• Calcium and phosphate levels in theextracellular fluid

• Levels of certain hormones with an effect onbone metabolism

• Mechanical stress on bone

Calcium and Phosphate Metabolism The skeletal bones contain 99% of all the calcium in

136 / The Journal of Manual & Manipulative Therapy, 2001

the body13,15. Calcium is physiologically very important.Calcium salts provide structural integrity to the skeleton14.Calcium also plays an important role in blood coagula-tion15: calcium ions act a co-factor for the clotting fac-tors VII, IX, and X14. Calcium ions link the processes ofexcitation and contraction in skeletal and cardiac muscle.In secretory cells, cytosolic calcium connects the secre-tory vesicles to the plasma membrane allowing forexocystosis of cell products. The intracellular ionized calciumlevels also control the activity of key regulatory meta-bolic enzymes. Calcium activates phosphoenolpyruvate-carboxykinase and inhibits pyruvate-kinase, resulting inincreased gluconeogenesis in the kidney. In skeletal muscle,calcium enhances glucogenolysis by acting upon phos-phorylase-b-kinase14. Calcium also has an important rolein maintaining the membrane potential of excitable tis-sues, such as nerves and muscles9. Low intracellular ionizedcalcium concentrations increase nervous system excit-ability by increased permeability of the neuronal mem-brane to sodium. Hyperexcitable nerve fibers spontane-ously depolarize, eliciting tetanic contractions in the skeletalmuscles that they innervate. Increased central nervoussystem excitability may even lead to seizures14. Hypocal-cemic tetany is a situation in which low calcium bloodlevels cause extensive spasms of the skeletal muscles,especially in the extremities; the laryngeal muscle spasmsinduced by hypocalcemia can be fatal15. Increased serumlevels of ionized calcium depress central and peripheralneural excitability, resulting in mental sluggishness andhyporeflexia14. Forty percent of the serum calcium is boundto proteins: 90% to albumin and 10% to globulins. Thebinding to albumin is pH-dependent. Acidosis decreasesthis binding and leads to increased ionized serum cal-cium levels. Respiratory alkalosis as a result of hyper-ventilation causes increased binding: the resultant hy-pocalcemia explains complaints of perioral paraesthesiae,carpal muscle spasms, and even seizures14. Phosphates and phosphorus are found in many pro-teins, ATP, cAMP, and other compounds vital to cell function;(de)phosphorylation of proteins plays a role in the regu-lation of multiple cell functions15. The skeleton contains85-90% of all the phosphorus in the body15. Calcium is absorbed from food in the intestine15.Sufficient nutritional intake of calcium is critical to bonemaintenance13. Even a chronic mild dietary calciumdeficiency will cause a negative calcium balance and gradualloss of bone mass. In young individuals, approximately15-25% of the ingested calcium is absorbed; in the eld-erly, this percentage declines. Augmented dietary calciummay be necessary during the adolescent growth spurt andearly adulthood when a peak bone mass is achieved, andduring pregnancy and especially lactation13. If duringpregnancy the mother’s diet is deficient, the developingfetus tends to have priority at the mother’s expense16.Insufficient calcium intake is common: only 15% of girlsand 53% of boys actually meet the recommended mini-

mal daily allowance (RDA) of 1200 mg for people betweenages 11 and 2416. As we will discuss later, vitamin D3 playsan important role in the active transport of calcium acrossthe intestinal wall. Other nutrients may affect calciumabsorption. Substances such as phosphates or oxalates,which form insoluble salts with the Ca2+-ions, will de-crease intestinal absorption15. Alkalis in food favor theformation of insoluble calcium soaps, again decreasingabsorption15. Overconsumption of fatty acids producesoxalates and phytates; these substances will decrease theaction of anti-oxidants, increasing the oxydative bindingof free radicals to calcium, thereby preventing its absorption9.High quantities of dietary fiber will also decrease calciumabsorption9,17. A high protein diet increases calciumabsorption in adults15. Phosphorus is absorbed from dietary sources in theduodenum and the small intestine. Vitamin D3 also playsa role in increasing absorption. Unlike in the case of calcium,the amount of phosphorus absorbed increases linearlywith dietary intake15. After crossing the intestinal wall, most of the cal-cium is deposited in the skeletal bones. From here, it iscontinually released to maintain appropriate blood lev-els7,12,15. Approximately 500 mmol per day is released intothe bloodstream from the interstitial fluid by diffusionof calcium ions into the hydration shell of the hydroxy-apatite crystals12,15. A small amount of calcium (7.5 mmolper day) is released into the bloodstream as a result ofcontinuous bone remodeling15. Small amounts of calciumare excreted through the kidneys, but most of the cal-cium is re-absorbed (98-99%), mainly in the proximaltubules of the kidney (60%), and to a lesser extent in theascending limb of the loop of Henle and in the distal tubule(40%). Some nutrients affect renal calcium re-absorp-tion. Excessive protein intake increases urinary excre-tion4,14,18. Excessive intake of refined sugar increases urinarycalcium excretion by altering renal tubular calcium re-absorption14. Caffeine and alcohol can increase excretionby their diuretic action, flushing the system of calciumand other important nutrients9. Excessive sodium intakemay also impair calcium re-absorption14. Plasma phos-phorus is filtered in the glomeruli with an 85-90% re-absorption fraction15.

Hormonal Influences As we discussed earlier, 99% of the total body cal-cium is sequestered in the skeleton; this leaves 1% tocirculate in the extracellular and intracellular fluid13.Similarly, 85 to 90% of all phosphorus is contained inthe skeleton15. The biochemical roles of calcium requirethat its extracellular and intracellular concentrations bemaintained within a relatively narrow range14. The se-rum calcium and phosphate concentrations are maintainedby a flux of these two substances between the blood andthree organs: bone, kidney, and intestine14. Three hor-


mones are primarily responsible for regulating calciumand phosphate metabolism: 1,25-dihydroxy-cholecalcif-erol, parathyroid hormone, and calcitonin3,7,9,13-15. We willdiscuss these and other hormones and cytokines with aneffect on calcium and phosphate metabolism. A healthy diet contains vitamin D

3 or cholecalciferol9,12,15.

Vitamin D3, however, is not a vitamin in the strictest sense;i.e., it is not an essential dietary requirement as it isphotochemically produced in the high dermis and lowerepidermis12,14,15. Exposure to mid-ultraviolet radiation (250-310 nm) turns 7-dehydrocholesterol or provitamin D

3,

an inert precursor available in the skin, into previtaminD

3; over days, previtamin D3 undergoes a temperature-

dependent isomerization into vitamin D314. Vitamin D3 is

then hydroxylated twice before it becomes the activemetabolite 1,25-dihydroxy-calciferol or calcitriol: first inthe liver by the enzyme 25-hydroxylase to 25-hydroxycalciferol or calcidiol, and then in the kidneysby the enzyme 1-alpha-hydroxylase to calcitriol or 1,25-(OH)2D3

15. Calcitriol increases the active transport of calciumfrom the intestine by forming calbindin-D proteins, cal-cium-binding proteins that have been correlated withincreased transport of calcium across the intestinal epi-thelium15. It also increases the number of Ca2+-H+-ATP-ase molecules in the intestinal cells, molecules neededto pump calcium into the interstitium15. Calcitriol alsoincreases the active transport of phosphate ions from thesmall intestine and facilitates calcium and phosphate re-absorption in the kidneys13-15. Osteoprogenitor cells andosteoblasts, but not osteoclasts, have been shown to havereceptors for calcitriol14. Osteoblast-mediated activationof osteoclasts as discussed earlier stimulates overall bonecell function resulting in higher serum calcium andphosphate levels15. There is also some evidence that cir-culating monocytes as a result of interaction with calcitriolmay fuse into multinucleated macrophages resemblingosteoclasts14. Calcitriol also stimulates the production ofosteocalcin and alkaline phosphatase, which may play arole in the mineralization of osteoid14. High blood phos-phate and calcitriol levels decrease the activity of 1-al-pha-hydroxylase and, therefore, the production of addi-tional calcitriol15. Hyperthyroidism is associated withdecreased calcitriol production15. Anticonvulsants stimulatethe production of hepatic microsomal mixed oxidaseenzymes, which convert vitamin D metabolites into hy-droxylated, biologically inactive substances; this may explaindecreased mineralization in patients receiving prolongedhigh-doses of anticonvulsant medication14. Calcitonin andgrowth hormone increase calcitriol production. Prolac-tin, a hormone produced during lactation, increases theactivity of calcitriol, thus maintaining high calcium re-absorption rates during this time of increased calciumdemand15. Parathyroid hormone or PTH is produced in the chiefcells, the principal parenchymal cells of the parathyroidgland, cleaved into biologically inactive fragments in the

liver, and then excreted through the kidneys9,14, 15. PTHacts on the lacunar osteocytes: stimulation results inosteocytic osteolysis, a rapid mobilization (within min-utes) of bone mineral by these osteocytes in response toPTH14. PTH also results in osteoclastic resorption, whichis more delayed; it may take hours to days14. Osteoclastshave no PTH cell membrane receptors: PTH stimulatesreceptors on osteoblasts, which in turn mediate osteo-clastic activity13. PTH also stimulates osteoclastic pre-cursor cells to differentiate into the multinucleated os-teoclasts14. The overall result of this bone cell stimula-tion is increased calcium and phosphate mobilization fromthe bone9,15. PTH is believed to influence bone cell activ-ity by stimulating membrane adenylyl-cyclase to formcAMP and by promoting calcium influx into the bone cells14.PTH also decreases phosphate re-absorption, increasesrenal calcium re-absorption, and increases calcitriolproduction7,14,15. PTH production is self-regulatory throughtwo negative feedback loops. The parathyroid glands havecell membrane receptors for calcium ions: high bloodcalcium levels will decrease PTH production14,15. Highcalcitriol levels, partly the result of high PTH levels, willalso decrease PTH production by decreasing the produc-tion of a precursor to PTH14,15. Epinephrine andglucocorticosteroids stimulate PTH secretion; hypomagnesiadecreases production of PTH14. Intermittent PTH secre-tion increases osteoblastic activity and stimulates remodelingresulting in increased bone growth. However, a chronicincrease in circulating PTH results in a net bone resorp-tion and the formation of large osteoclast-filled cavitiesin the bone, a condition known as classic osteitis fibrosacystica14. Calcitonin is excreted by the parafollicular or C[clear]-cells of the thyroid gland in response to high serum calciumlevels9,14,15. Osteoclasts have cell membrane receptors forcalcitonin14. Calcitonin decreases calcium and phosphateconcentrations by directly inhibiting osteoclast activityand by increasing calcium excretion in the urine9,14,15.Increased calcitonin levels during pregnancy and lacta-tion protect the mother’s bone density, as the growingskeleton of the baby and calcium loss with lactation canbe major drains on the calcium blood levels of the mother15. Other hormones and substances may also have aneffect on bone remodeling. Estrogen has a bone-sparingeffect. Cell membrane receptors for estrogen have beenfound on osteoblasts3,14,15. Estrogen inhibits secretion ofIL-1 and tumor necrosis factor-alpha (TNF-alpha). Thesecytokines play a role in the development of osteoclasts3,9,15.Estrogen decreases IL action by affecting their receptoron the osteoclastic cell membrane9. It increases TGF-betaproduction: this substance increases apoptosis or geneticallyprogrammed cell death of osteoclasts15. TGF-beta alsostimulates differentiation and replication of osteoblasticprogenitors and inhibits osteoclastogenesis14. Estrogenreduces prostaglandin E2 (PGE2) levels14. Estrogen andtestosterone decrease the sensitivity of bone cells to PTH9.


Estrogen also stimulates the parathyroid glands to in-crease production of calcitonin and facilitates PTH ac-tion in the kidneys4,9,14,15. Glucocorticoids lower serum calcium levels by in-hibiting osteoclastic activity. However, long-term elevatedglucocorticoid levels, as occur with Cushing’s syndromeor may occur iatrogenically as a result of overmedication,will cause decreased BMD by inhibition of protein syn-thesis in osteoblasts, impaired maturation ofosteoprogenitor cells into osteoblasts, increased osteo-clastic activity, decreased vitamin D-dependent intesti-nal calcium absorption, and increased renal excretionof calcium and phosphate ions7,15. Glucocorticoids alsosuppress gonadal estrogen and testosterone productionand directly stimulate PTH production14,16. PTH productionis also increased as a result of the secondary hyperpar-athyroidism associated with chronically decreased se-rum calcium levels13,14,16. Corticosteroids may also di-rectly decrease bone formation by their inhibitory ef-fect on collagen synthesis13. In hyperthyroidism both thyroxine and tri-iodothyronine may cause increased bone resorption,hypercalcemia, decreased PTH-levels, decreased calcitriollevels, and decreased intestinal calcium absorption14.Thyroid hormones also favor increased urinary excre-tion of calcium15. The net result of hyperthyroidism isincreased bone remodeling with a loss of bone mass4,16.Of course, excessive thyroid hormone levels may alsobe the result of overreplacement for hypothyroidism14. Growth hormone increases both urinary excretionand intestinal absorption of calcium: the net result isincreased calcium absorption15. Somatomedin C, or IGF-I, is a growth hormone-dependent peptide produced inthe liver and in bone14. It is mitogenic for chondrocytesand osteoblasts, stimulates osteoblast activity, and in-creases protein synthesis in bone9,14,15. Administrationof growth hormone to deficient children stimulates bonegrowth via somatomedin C production. It also increasesintestinal calcium absorption by way of a vitamin D-independent mechanism and it increases renal tubularphosphate re-absorption14. Insulin increases bone formation, but untreated dia-betes may result in bone loss15. This may be related tothe diuresis of calcium in untreated and poorly controlleddiabetes with secondary hyperparathyroidism as a resultof the resultant hypocalcemia13. Heparin, released by mastcalls or administered therapeutically, enhances collage-nase activity and may have a resorptive effect on the bonematrix13. We discussed earlier how the bone matrix con-tains small quantities of TGF-beta, IGF, IL-1, IL-6, andBMP 1-613. These cytokines may also be produced andreleased by local monocytes and lymphocytes13. We al-ready discussed the role of TGF-beta. IL-6 is producedby osteoblasts in response to PTH, calcitriol, IL-1, andTNF-alpha. The latter two substances may be releasedfrom the matrix during bone resorption. IL-6 stimulates

the early stages of osteoclastogenesis; its production isinhibited by estrogen and testosterone. IL-1 is alsoosteoclastogenic but, unlike IL-1, its production is notregulated by sex hormones13. BMP 1-6 modulate boneremodeling with their mitogenic, differentiating, andchemoattracting properties13. Osteoblasts have receptorsfor PGE2: stimulation allows osteoclasts access to the boneas a result of osteoblast contraction and osteoblastic os-teoid degradation as discussed earlier13.

Mechanical Loading Gravity and muscular contraction both cause me-chanical deformation of bone9. Cellular function nor-mally generates bio-electric effects independent ofmechanical stress, but mechanical deformation resultsin stress-generated electrical potentials, superimposedon this normal bio-electric activity. There are two typesof stress-generated potentials: piezo-electric and streamingpotentials13. In piezo-electric materials, potentials areproduced by strain in the organic components of thematerial, i.e., collagen and proteoglycans. Streamingpotentials are the result of electrolyte fluid flow pro-duced by deformation of the tissue13. Compression causesan increase in negative charges and increased osteoblasticfunction; tension results in increased positive chargeswith increased osteoclastic function9. The role stress-generated potentials play in bone remodeling remainsuncertain13. The response to mechanical load is specific to thebone being loaded19. Mechanical load stimulates bonecells to increase synthesis of prostacyclin (PGI2), PGE2,glucose-6-phosphate-dehydrogenase, and RNA withinminutes of loading9,19,20. PGE2 and PGI2 mediate the re-sorptive response to cytokines and growth hormone inbone: thus, intermittent mechanical force through theincreased production of these substances will stimulatebone formation20. As discussed earlier, IL-1 and IL-6 stimulate boneresorption. Strenuous exercise increases the IL-1 pro-duction. This effect, however, is less pronounced in trainedversus untrained individuals. Furthermore, trained in-dividuals have lower average levels of cytokines thanuntrained people. Regular exercise may result in loweraverage cytokine levels, which in turn could result in areduced stimulation of osteoclasts20. The relative impor-tance of all these mechanisms is unclear at present20.Mechanical loading through exercise has the potentialto be a safe and effective way to avert or delay the onsetof osteoporosis. The use of exercise as an intervention isdiscussed in the second article in this series.

Classification Osteoporosis can be classified as primary or second-ary. Included in the primary category are idiopathic,


postmenopausal, and senile osteoporosis. Senile osteoporosisis also known as involutional osteoporosis. Secondaryosteoporosis is osteoporosis caused by other disorders3,7.

Primary Osteoporosis Idiopathic osteoporosis is osteoporosis of an unknownetiology that occurs in pre-menopausal women and youngto middle-aged men with normal gonadal function4,7.Juvenile idiopathic osteoporosis is a usually self-limit-ing disease affecting previously healthy, prepubertal childrenbetween ages 8 to 14. It usually runs an acute courseover a period of two to four years, during which timeskeletal growth stops. Multiple fractures may occur inboth the appendicular and axial skeleton. The disease maybe mild, affecting only one to two vertebrae, or it can besevere, resulting in deformity of virtually all the lumbarand thoracic vertebrae and multiple extremity fractures.Remission is spontaneous with resumed linear and ra-dial growth. A main goal of treatment is to protect thespine until such remission occurs16. The two most important factors in the development(and prevention) of osteoporosis are the peak bone mass(PBM) and the rate of bone loss after attaining PBM9,13.PBM is the maximal bone mass that an individual expe-riences during his or her lifetime9. Bone mass peaks afterskeletal maturity, somewhere in the third decade13.Boissonnault7 placed PBM between the ages of 25 and 35years old. However, nearly maximal BMD may already beachieved in both the lumbar spine and the femoral neckbefore the end of the second decade. Gains during a person’s20s are small when compared to the dramatic gains duringadolescence. In girls, the rate of gain in the lumbar spineand femoral neck already starts to decline two years af-ter menarche. By age twelve, girls have already achieved50% of their adult bone mineral content and 80% of theiradult BMD16. This prompted Gleeson16 to view osteoporosisas a pediatric disease rather than as a disease of middleto old age. (The implications of this for prevention ofosteoporosis are discussed in the second article.) After attaining PBM, bone formation rates remainconstant, but bone resorption rates increase: in the de-cade after age 40 men lose 0.5-0.75% of their bone massevery year, while women lose 1.5-2% per year13. The rateof bone loss increases dramatically after menopause.Boissonault7 reported a bone loss of 11% in the first 5years after menopause and an additional loss of 5% inthe next 20 years. Kaplan et al13 reported bone loss of upto 3% per year. McCloy17 reported a postmenopausal boneloss of 3 to 5% per year for a period of 10 to 15 years.Typical for postmenopausal or type I osteoporosis is se-lective loss of cancellous bone9. The metabolically lessactive compact bone is less affected3. Cancellous boneloss may be as high as 7% per year in the first 5 yearsafter menopause9. Postmenopausal osteoporosis is thoughtlinked primarily to a decreased production of estrogen7.

We discussed earlier the bone-sparing effects of estro-gen. Postmenopausal women still produce estrogen, buttheir levels are below those of age-matched men andpremenopausal women13. However, the estrogen levelsof osteoporotic and non-osteoporotic post-menopausalwomen are similar9. Bottomley9 hypothesized an inter-action with other factors, suggesting a role for dietarycalcium intake and absorption and activity and exerciselevels. Type-II or senile osteoporosis occurs in both men andwomen over the age of 70. It is characterized by a pro-portionate loss of cancellous and compact bone. This isin contrast to the mainly cancellous bone loss in type-I osteoporosis9. With aging, the number of osteoblastsdecreases. This may be related to decreased levels of growthhormone. Growth hormone stimulates the productionof IGF-I in the liver and locally in the osteoblasts. As wediscussed, IGF-I plays a role in mitogenesis and activityof osteoblasts14,21. Aging also results in decreased levelsof TGF-beta and testosterone9,14. Type-II osteoporosis isalso associated with a primary defect in the kidney’s abilityto produce calcitriol. This may be related to a primaryimpairment in renal 1-alpha-hydroxylase function21.Decreased calcitriol levels result in decreased intestinalcalcium absorption and a secondary hyperparathyroid-ism and hyperthyroidism3,9.

Secondary Osteoporosis In the sections on calcium and phosphate metabo-lism and on hormonal influences above, we discussed anumber of causes for secondary osteoporosis. Osteoporosiscan be caused by nutritional deficiencies, endocrinopa-thies, gastrointestinal diseases, bone marrow disorders,connective tissue diseases, medications, and a numberof other problems3,7. Nutritional deficiencies of calcium and vitamin D cancause secondary hyperparathyroidism, resulting in increasedbone loss, especially in the elderly22. In 1994, the Na-tional Institutes of Health’s Consensus Development Panelon optimal calcium intake as cited by Lane22 made rec-ommendations regarding calcium RDA (Table 2). Wediscussed earlier the calcium-deficient diet among ado-lescent boys and especially girls. Even though this willnot cause osteoporosis, it may decrease peak bone mass,an important determinant of osteoporosis risk later inlife. Dairy is the most important dietary source of cal-cium; however, up to 65% of the elderly are lactose-in-tolerant22. Calcium supplementation is especially importantin the elderly: supplementation does not preventperimenopausal bone loss, but it may stabilize bone mineralcontent in people over 65, presumably by preventingsecondary hyperparathyroidism22. It is important to knowwhen educating patients regarding calcium supplemen-tation that calcium is best absorbed when the doses arespread throughout the day: doses over 500 mg may be


wasted by the gastrointestinal tract22. We already discussedthe negative effect that diets high in phosphates, oxalates,alkalis, fatty acids, and dietary fibers have on intestinalcalcium absorption. Excessive dietary intakes of protein,refined sugar, caffeine, alcohol, and sodium may increaseurinary calcium excretion. Vitamin D deficiency is com-mon in the housebound elderly. Especially during thewinter months, photochemical production in the skin maybe insufficient. RDA is 400 IU per day, but this may needto be increased to 800 IU in the debilitated, homeboundelderly22. Vitamin D at supra-physiologic levels, however,can stimulate bone resorption and cause hypercalcemia4,22. Many endocrine diseases have the potential to causeosteoporosis. We already discussed the effects of diabe-tes, hyperthyroidism, hyperparathyroidism, andhypercortisolism (Cushing’s disease). Hypogonadism anddecreased testosterone production may affect bone massin men3. Cystic fibrosis is often associated with delayedpuberty and hypogonadism in boys16. Estrogen deficiencyin women may occur as a result of menopause, but it canalso occur with premature ovarian failure or as a resultof oophorectomy3. Anorexia nervosa can cause decreasedbone mass as a result of estrogen deficiency, but also dueto the associated overproduction of endogenousglucocortocoids, generalized malnutrition, and calcium

deficiency16. Hypothalamic amenorrhea can produce es-trogen deficiency among female athletes and especiallyrunners4. Periods of amenorrhea or oligomenorrhea duringadolescence and early adulthood have been shown to resultin bone loss of up to 2% per year; return to a normalmenstrual cycle stops further bone loss22. Gastrointestinal disorders can interfere with theabsorption of calcium, phosphate, and other importantnutrients. They may also interfere with the metabolismof hormones important for maintaining calcium andphosphate homeostasis. Bone marrow disorders may affectthe formation of the cellular component of bone andconnective tissue disease may affect production of theorganic matrix of bone. We already discussed a numberof medications that may affect bone metabolism. Exces-sive alcohol intake not only has a diuretic effect result-ing in increased calcium excretion; it may also directlyinhibit osteoblastic activity and increase serum gluco-corticoid levels. It is often associated with malnutrition.Alcoholism is the most common cause of osteoporosisin men17. Cigarette smoking has been associated with a5 to 10% reduction of bone mass in women7. This maybe the result of inactivation of estrogen in the liver, increasedresistance to calcitonin, interference with osteoblasticfunction, a smoking-related weight reduction, and inad-equate intake of nutrients7,17. Women who smoke appearto enter menopause earlier; smoking also seems to ne-gate some of the positive effects of hormone replacementtherapy in postmenopausal women17. Chemotherapeuticagents generally may negatively affect bone metabolism;the exception is tamoxifen. Tamoxifen is an estrogen-antagonist used in the treatment of patients with breastcancer. It is a selective estrogen receptor modulator (SERM)and as such it is recognized by the bone cells as estro-gen22,23. It has been shown to be 70% as effective as es-trogen in preventing osteoporosis22. Other SERMs beingdeveloped for the treatment of osteoporosis are discussedin the second article.

Conclusion Osteoporosis and osteopenia affect a large portion ofthe population. Both sexes are affected, but women aremore prone to decreased BMD than men. Bone remodel-ing is the result of activity of the cellular component ofbone. This activity is regulated by a complex interactionof extracellular calcium and phosphate levels, hormonalinfluences, and mechanical stress to the bone. There arethree types of primary osteoporosis: idiopathic, postmeno-pausal, and senile osteoporosis. Secondary osteoporosiscan be the result of a variety of nutritional deficiencies,endocrinopathies, gastrointestinal diseases, bone marrowdisorders, connective tissue diseases, medications, and otherproblems. The information presented in this article willallow for better understanding of diagnosis and treatmentas discussed in the second article in this two-part series.

Table 2. National Institutes of Healthrecommendations for optimal daily calcium intakeModified from Lane (1997)22

Target Optimal dailypopulation calcium

intake (mg)

Women• 25 to 50 years old 1000• 50 to 65 years old

(postmenopausal)Taking estrogens 1000No estrogens 1500

• Over 65 years old 1500• Pregnant and nursing 1200-1500

Men• 25 to 65 years old 1000• Over 65 years old 1500

Adolescents to young adults(11 to 24) 1200-1500

Children• 1 to 5 years old 800• 6 to 10 years old 800-1200

Infants• Birth to 6 months old 400• 6 months to 1 year old 600


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AcknowledgementThis article was written in partial fulfillment of the

requirements for the Doctor of Physical Therapy degree

at the University of St. Augustine for Health Sciences inSt. Augustine, FL. I would like to thank my faculty ad-visor, Dr. Jude C. Nwoga, PhD, for his help and advice incompleting this project.

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osteoporosis: epidemiology, histology, bone remodeling, and classification

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