YEARBOOK OF PHYSICAL ANTHROPOLOGY 33:151-194 (1990)

Osteoporosis: Etiologies, Prevention, and Treatment

WILLIAM A. STINI
Department of Anthropology, University of Arizona,
Tucson. Arizona 85721

KEY WORDS

Bone, calcium homeostasis, industrialized countries

ABSTRACT

W-ith the steady increase in life expectancies occurring in

industrialized countries have come major changes in the causes of morbidity
and mortality. The greatest burden on the health care delivery systems in
these countries has shifted from the treatment of infectious diseases to
extended care of degenerative conditions. One such condition of increasing
widespread concern is osteoporosis. Chronic bone loss leading to fractures
and secondary infections has become a major problem in the United States,
and has been estimated to cost $6 to $8 billion annually.
The etiology of osteoporosis is complex, depending upon the interaction of
nutritional, endocrinological, and local factors that are subject to a variety
of genetic and environmental influences. The stringent requirement of
maintaining calcium homeostasis places heavy demands on the primary
reservoir of calcium, the skeleton, when intake andlor absorption are inadequate. Inactivity, depriving bone of its weight-bearing function, also initiates bone resorption. Under normal circumstances in the young adult,
bone is maintained through continual, balanced turnover of mineral and
calcium. When this balance is upset, loss of bone can be slow or rapid,
reversible or irreversible. The trabecular compartment with its high surface-to-volume ratio is most rapidly mobilized, but cortical bone is ultimately resorbed as well.
Involationaf osteoporosis is conventionally designated as either type i
I postmenopauqali or type I1 senile:. Women are affected by both and, because of a generally less-robust skeleton, experience risk of fracture earlier
than men on the average.
The hormonal and physiological factors involved in the regulation of normal bone physiology and the factors leading to loss of bone mass constitute
a n area of active research that is casting light on the fundamental mechanisms underlying bone growth and maintenance in the search for new avenues of prevention and treatment of osteoporosis.

Currently the fastest growing segment of the population of the United States is
the age group 85 years old and older (United Nations, 1986). The increasing numbers of elderly citizens of both sexes have changed the countrys demographic
profile but the proportion of women living to advanced age has had singular impact. In North America in 1984, males outnumbered females by about 1million (29
million to 28 million) up to the age of 15 years, but in the age group 65 years old
and older, females outnumbered males by 6 million (18 million women, 12 million
men) (Stini, 1987). Beyond age 65 years, the disparity in survival continues to
grow. In the age group 80 to 84 years, the death rate is currently 107.0 per 1,000
for males and 66.9 per 1,000 for females. Thus, the population of the United States
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is not simply aging, but is composed increasingly of aging women. The impact of
these demographic changes on the health care delivery system is already of widespread concern (Phillips et al., 1988).
Discussions of prioritization and rationing of medical services often center on the
degree to which society can afford to allocate scarce resources to the maintenance
of patients who are chronically impaired with little hope of recovery (Aaron and
Schwartz, 1990). As the demographic trends cited above produce a steady increase
in numbers of postmenopausal women in the population, the costs of care and
treatment of patients afflicted with one or another form of bone loss will increase
dramatically. The impact of this increase is already being felt in the United States
where the direct costs of the various forms of bone loss broadly subsumed under the
heading of osteoporosis were estimated to be in the range of 6-8 billion in 1986
dollars (Heaney, 1989a,b). In terms of the worldwide impact of the increased size
of populations at risk for osteoporosis, we are only seeing the tip of the iceberg. The
demographic trends p m d w i n g tbe high proportion of post:::eaopauaal wuiiieii iri
the Western industrialized nations are also being manifested in developing countries such as India. In the third world, the health care infrastructure is much less
prepared to cope with the problems of large numbers of patients suffering from
chronic and disabling conditions such as osteoporosis and hip fractures (Stini,
1987).
Why does the aging process produce increased risk of fractures? In order to
understand the relationship between aging and bone loss it is necessary to appreciate the dynamic nature of bone and its continual interaction with other tissues.
While the skeleton is most readily perceived as a rigid structural framework that
protects and supports the bodys soft tissues, its role as a reservoir of mineral and
as a buffer of the body fluids is equally important. In fact, the physiology and
biochemistry of bone are intimately linked to such important processes a s the
immune response, muscle contraction, and nerve impulse transmission in a variety
of ways. A major component of this interaction is ionic calcium, which is a major
secondary intracellular messenger and a regulator of muscle contraction. Calciums physiological importance preceded the evolution of bone and, not surprisingly, its physiological functions still hold a higher priority than its structural role.
Thus, the requirements of other systems are often met a t the expense of bone.
Osteoporosis, broadly defined a s the loss of bone, is best viewed as the result of
a perturbation of the dynamic equilibrium through which bone and other systems
satisfy their needs for calcium. It is therefore essential to approach the problem of
osteoporosis by the ascertainment of the role of calcium in human physiology and
the means hy which normal physiolagical levels of calcium are maint.ained. Ey
using this approach, i t can bc scen how Lhe cells aid tissues of bone are cxqnisite!:sattuned to the task of maintaining mineral homeostasis. It is also clear that there
are many etiologies by which osteoporosis can occur and, therefore, a range of
potential interventions. The present review will attempt to integrate the biochemical and physiological aspects of calcium metabolism with the cytological and histological characteristics of bone. The goal is to relate structure to function and,
ultimately, malfunction. If this is done successfully, the apparent contradictions
concerning the etiology of osteoporosis found in the rapidly expanding literature on
the subject will, to some degree, be less confusing.
CALCIUM

Physiological role
The calcium ion is now widely accepted a s the most fundamental regulator of
intracellular processes of all living organisms (Ebashi, 1988). The normal calcium
concentration in human blood is 10 mg%. The tolerable range is generally stated
as 7-13 mg%. Below 7 mg% there is danger of tetany and above 13 mg% soft tissue
calcification can occur. The physiological importance of calcium derives from a
number of essential functions that depend upon its presence in its ionic form.
Calcium deficiency inhibits cardiac excitation-contraction coupling. The result is

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Osteoporosis: Causes and Treatment

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a decline in contractile force without major change in single fiber action potentials
(Fleckenstein, 1988). Calcium-dependent myofibrillar adenosine triphosphatase
(ATPase) transforms phosphate bond energy into mechanical work. Channels in
the surface membranes of many cells are formed by integral membrane proteins
forming pores that allow calcium to enter the cell. The number and types of channel are associated with particular kinds of tissue. The more rapid Tchannels and
the slower L channels are both found in smooth, cardiac, and skeletal muscle.
Activation or blockage of these channels can have profound effects on heart rate
and blood pressure (Bolton et al., 1988). Neurons display three types of channels
(Nowycky et al., 1985). In muscle contraction a s well a s in cytoplasmic streaming
of cells, calcium acts a s a regulator through its interaction with contractile proteins. In skeletal muscle, the attraction of calcium to a specific site on the troponin
molecule potentiates the movement of tropomyosin that in t u r n allows actin and
myosin to interart, hydrolying adenosine triphosphate (-4TP) to re!czsc ccergy
during the contraction cycle.
Calcium ions play a major role as a n intracellular messenger, often acting in
concert with cyclic adenosine monophosphate (AMP) to determine the reactions of
glandular cells that influence a wide range of physiological mechanisms (Rasmussen, 1989). Cytotoxic T-cells also use calcium ions in the mechanisms leading up to
the lysis of target cell membranes (Young and Cohn, 1988).

Maintenance of a calcium reservoir

Commensurate with the importance of calcium in so many essential processes,
the creation and mobilization of a calcium reservoir has a high priority. Short- and
long-term withdrawals of calcium to maintain normal serological concentrations
are facilitated by a series of responses beginning with the freeing of protein-bound
calcium circulating in the blood and ultimately progressing to the resorption of
calcium from the lamellae of cortical bone. Endocrine hormones emanating from
the thyroid, parathyroids, adrenals, ovaries, and testes all participate under various circumstances in the movement of calcium from one tissue compartment to
another. When the dietary intake of calcium is adequate and when absorption is
normal, bone turnover occurs a t a relatively low rate. When calcium intake, bioavailability, or absorption fall below normal levels, when perturbations in endocrine function occur, and when inactivity or a variety of physiological malfunctions
upset serum calcium balance, turnover rates increase and bone mineral is resorbed.
The calcium content of a n adult, human body will range from 1,200 g ti? 1,500 g
(Norman, 1990). Ninety-eight percent, of total calcium i s found in t.he skeletor?:
which weighs from 2.8 to 4.0 kg, organic and inorganic components combined.
Womens values cluster near the low end of this range and mens near the upper
end although there is a substantial zone of overlap of male and female distributions. In order to attain adult skeletal mass, it is necessary to maintain a net
positive balance of 100 mg per day from birth to the onset of puberty (Garn, 1981;
Norman, 1990). The rate of retention during puberty climbs to about 200 mg per
day in females and about 280 mg per day in males. Since absorptive efficiency for
calcium varies, the amount of dietary calcium needed to sustain these rates of
retention could require a n intake of a s little as 400 mg per day for a n adolescent
male with a n absorptive efficiency of 7596, to as much as 1,200 mg per day for a n
adolescent male with a n absorptive efficiency of 25% (Garn, 1981). In most instances, the latter value is not sustained. It is generally believed, however, that the
efficiency of absorption declines with increasing dietary intake and therefore the
higher efficiencyllow intake example may be the more realistic one.

Calcium turnover
If a normal adult male consumes 1,000 mg of dietary calcium per day, approximately 700 mg will be absorbed in the intestine. However, 600 mg will normally
be secreted into the intestinal lumen resulting in a net uptake of only 100 mg.

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tVo1. 33, 1990

Fig. 1. Calcium and phosphorus homeostasis. Dietary intake is 1,000 mg per day calcium and 900 mg
per day phosphorus. Calcium entries are ~n rectangles and phosphorus entries are in ovals (from Norman, 1979).

Therefore 900 mg of ca!ciam i s lost in the feces, The newiy absorbed 700 mg will
eventually enter the exrraceiiuiar fiuid e o m p a r ~ ~which
e ~ t will maintain a pooi
of approximately 900 mg of calcium. Over a period of time much of the calcium in
the extracellular fluid compartment will enter cells, becoming part of the 1,000 mg
intracellula~~
pool of calcium. Some calcium from extracellular f h i d will reenter
the blood, pass through the kidney, and be lost in the urine. This loss will average
40 mg per day. About 60 mg per day will also be lost in sweat. Thus, under
conditions of homeostatic balance, the 1,000 mg of calcium ingested in the diet is
offset by 900 mg lost in feces, 40 rng in urine, and 60 mg in sweat (see Fig. 1).
The calcium present in bone is also in a continual state of turnover. The rapidly
exchangeable component of bone mineral permits the turnover of 20,000 mg of
calcium per day while the more slowly exchangeable component contributes a n
additional 300 mg. The total exchangeable component o f bone includes a pool of
4,000 mg of calcium present in the skeleton at any given time. The stable component of bone is also far from inert, although the proportion of turnover i s much
lower than that of the exchangeable component. Of the approximately 1 kg of
stable bone mineral, about 300 mg will be added each day by accretion while 300
mg is lost by resorption. The dynamic nature of the calcium pool is such that many
factors can alter turnover and produce either a positive or negative imbalance.

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Osteoporosis: Causes and Treatment

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Factors that alter intestinal function either by increasing or decreasing absorption

or secretion can lead to substantial alterations in the rate andlor direction of
turnover. The same can be said for changes in kidney filtration and reabsorption.
Increased excretory loss of calcium will result in a reduced concentration of calcium in the extracellular fluid which must then in most cases be compensated for
by increased withdrawal from bone (Hegsted, 1986).
The entire extracellular pool turns over between 40 and 50 times per day. The
glomerular filtration rate for calcium is on the order of 10,000 mg per day but renal
tubular reabsorption is highly efficient accounting for the low rate of calcium loss
normally occurring in the urine. Even when serum calcium levels rise excessively,
compensatory excretion of urinary calcium rarely exceeds 600 mg per day. However, when intake or absorption of calcium fall to very low levels, continuous loss
of calcium in the urine can have a significant effect that will be reflected in loss of
honc ~ ~ , i n ~
the
r dultimate
,
reservnir for the maintenance of calcium homeostasis
(Nordin, 1986).

Calcium absorption
Calcium is usually ingested in the form of one of its compounds. In some areas,
drinking water may provide some calcium in ionized form, but this is usually not
a significant proportion of the overall daily requirement. The efficiency with which
ingested calcium is absorbed varies for a variety of reasons. Even large quantities
of ingested calcium may be insufficient (Barrett-Connor, 1989) under certain conditions. Lactose intolerance and maintenance of a low-cholesterol, low-calorie diet
may have the side effect of limiting calcium intake so that even an efficient calcium absorber is unable to derive enough calcium from the diet to offset losses to
sweat and urine (Griessen et al., 1989).
The presence of specific compounds in particular foods also affects calcium absorption. For example, phytates present in the gut due to the digestion of bran can
interfere with absorption by chelating calcium and carrying it through the intestine to be lost in the feces. Although considered beneficial for many reasons, highfiber diets have the potential to reduce calcium absorption by increasing the bulk
of the intestinal contents and reducing transit time during which absorption can
occur. Although spinach is rich in calcium, it is poorly absorbed in the human
intestine because of the simultaneous presence of oxalates (Heaney, 1988). Animal
experiments have shown that the oxalates of spinach reduce calcium absorption in
other species as well (Poneros-Schneier and Erdman, 1989; Weaver et al., 1987;
Wien and Schwartz, 1983): On the other hand, when kale?a low-oxalate vegetable
containing pectines and other plant.fibers typical of greens is consumed, high levels
of calcium absorption occur. Heaney and Weaver (1990), using an intrinsically
labeled kale were able to demonstrate fractional calcium absorption of 40%, equal
or superior to that associated with milk calcium. Kale is one of the varieties of
Brassica oleracea, several members of which (including broccoli) are known to be
rich in calcium. Other members of the genus Brassica having greens rich in absorbable calcium are turnip, collard, and mustard. All of these are characterized by
low oxalate content.
Recent work suggests that interactions between different ingested foods can
affect calcium absorption. For example, Heaney and Weaver (1989) found that
when milk and calcium oxalate were ingested together, oxalate did not interfere
with the absorption of milk calcium. The oxalate calcium was absorbed more
poorly than the milk calcium but still better than spinach calcium.
In an effort to measure the effect of calcium supplements and milk on calcium
balance, Lewis et al. (1989),conducted a metabolic balance study on 8 adult males
over a 56-day period. They found that milk and supplements had no appreciable
effect on calcium balance in their subjects. This would seem to contradict the
results of a study conducted by Schuette et al. (1989), who found that lactose or its
component sugars enhance jejunal calcium absorption in proportion to their effect
on fluid absorption. The apparent contradiction may arise from potential differ-

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TABLE 1 Prevalence of gastric

atrophy with increasing age
Age (years)
60-69
70-79
,80

Percent atrophic
24
32
37

ences in the degree to which lactose was broken down to its constituent sugars,
glucose and galactose. The enhancement of calcium absorption by glucose in the
human intestine has been reported by a number of investigators (Monnier e t al.,
1978; Norman et al., 1980; Wood, 19871. Wood (1987) also noted t h a t glucose
polymers enhance calcium bioavailability, confirming the role of glucose while not
necessarily excluding dii eiilidixiug effecL by galactose.
It is generally accepted that calcium supplements are best absorbed when taken
with a meal. In a recent study, Heaney et al. ( 1 9 8 9 ~found
)
that the co-ingestion of
calcium supplement and a light meal of varied composition enhanced calcium
absorption efficiency by 10%to 30%.The solubility of the calcium supplement will
of course affect its absorption efficiency. Calcium carbonate, the most-frequently
used form of calcium supplement, is not the most soluble. Nor are calcium phosphate, calcium gluconate, calcium fluoride, or calcium chloride. The most available calcium is that taken in the form of calcium citrate or calcium pidolate (Bellony et al., 1989; Harvey et al., 1988). There is also evidence t h a t the presence of
certain amino acids, one of them L-lysine, enhances calcium absorption (Civitelli
e t al., 1989).

The role of the gastrointestinal tract

Because the solubilization of calcium compounds is essential for absorption, the
normally acid environment of the stomach is a n important component of calcium
digestion. Thus, conditions such as achlorhydria, quite common in older people,
have the affect of reducing absorption efficiency. The use of aluminum-based antacids can simulate or aggravate this reduction in stomach acidity.
The absorptive capacity of the intestine declines in old age for a number of
reasons, not all affecting the absorptive efficiency relating to calcium, but nonetheless of importance in bone maintenance. Gastric secretion of both hydrochloric
acid and of pepsin decline with age. Also, the secretion of intrinsic factor decreases.
reducing the absorpkon of vitamin BIZ.Pancreatic secretion also diminishes. resulting in lower concentrations of severai important digestive enzymes in the
small intestine. Liver size and blood flow decline, additionally reducing the rate of
absorption and utilization of nutrients. Although fat absorption does not appear to
decrease substantially with age, i t does appear that the ability to cope with very
high intakes of fat is reduced. Similarly, normal protein intake is absorbed as well
by the older intestine as in early adulthood, but at intakes exceeding 1.5 gikg,
nitrogen secretion increases. Lactase production declines and consequently lactose
intolerance increases. The beneficial effects of glucose in calcium absorption are
therefore reduced in many older people. There are indications t h a t diets containing
mixtures of carbohydrates are absorbed less effectively in the older intestine, possibly indicating a change in gut flora. The rise in pH of the proximal intestine
following reduction in gastric acidity potentiates bacterial overgrowth. The increasing prevalence of gastric atrophy producing these changes with increasing
age is shown in Table 1.
As a result of the changes taking place in the intestine, the ability to increase
absorptive efficiency when calcium is present in low concentrations in the gut is
lost in old age. Consequently, the minimum quantity of ingested calcium needed to
maintain homeostasis rises with age. The system of calcium absorption is saturable a t all ages, there being a n upper limit to the amount absorbed when very large
amounts are ingested. It is estimated that in a normal young adult 400-500 mg

Stinil

Osteoporosis: Causes and Treatment

400

157

LACTATION

PREGNANCY

. .

1100

-200

Ca INTAKE ( W d a y )

Fig. 2. Calcium absorption as related to calcium intake and physiological states (from Norman, 1990).

must be ingested per day to effect a net absorption of 100-150 mg (Norman, 1990).
Because several factors lead to decline in absorption in older people, the amount of
calcium ingested should be increased in compensation.
Calcium absorption rates also undergo changes at other stages in human life.
The most dramatic shifts occur during puberty and again during pregnancy and
lactation (Nordin, 1988). These changes indicate a n adaptive capacity to alter
absorption efficiency when the need is greatest (see Fig. 2).

Population differences in calcium intake

Comparison of populations show that there is a broad range of calcium intake in
different parts of the world. Sustained intakes ranging from a low of -300 mg!day
in parts of Japan and India to as high as 1.300 mglday in Finland demonstrate that
the human intestine is capable of adjusting absorption rates not only in response
to changing needs experienced a t different stages of the life cycle but also in
response to sustained demands imposed by environmental factors (Food and Agricultural Organization, 1961, 1976). Much still remains to be learned about the
extent to which the aging intestine can make adaptive changes to maintain calcium homeostasis.
Because of the multiplicity of factors capable of altering the amount of calcium
absorbed, the recommended daily intake remains a n area of considerable disagreement. The value of calcium supplementation is not universally accepted, especially
with respect to the most widely used calcium carbonate tablets. However, there is
general agreement that adequate intake of calcium is important up to the attainment of peak bone mineral content (Matkovic et al., 1987; Tylavsky et al., 1989).
More will be said on recommended daily allowances in a later section.
The role of vitamin D in calcium absorption
Vitamin D stimulates calcium absorption in the intestine at all levels of calcium
intake. Its stimulatory effect is most pronounced when calcium intake is low and
i t declines when calcium is abundant (Norman, 1990). Some calcium absorption
occurs even in the absence of vitamin D, but i t would not be sufficient to maintain

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IFig. 3. The vitamin D endocrine system and the maintenance of homeostatic calcium level (from
Norman, 1990).

homeostasis on a sustained basis. Vitamin D is produced in the skin when ergosterol is irradiated by ultraviolet light. Relatively little exposure of the skin is
needed to satisfy normal physiological requirements. With ultraviolet radiation
ergosterol is converted to cholecalciferol (vitamin D3), which enters the circulation
and is carried to the liver (see Fig. 3 ) . There it is hydroxylated, to produce 25OH-D,. The 25-hydroxycholecalciferolreenters the circulation and is carried to the
kidney where i t is again hydroxylated. Two forms of dihydroxycholecalciferol
emerge from the kidney. These are 1,25(OH),D3 and 24,25(OH),D,. Thus, at any
time, four forms of vitamin D, may be present in the blood. Both of the hydroxylases producing the two forms of dihydroxycholecalciferolare found in mitochondria of proximal tubules of the kidney. They are enzymes with properties similar
to other steroid hydroxylases present in adrenals, ovaries, and testes (Deluca,
1979).
Receptors for 1,25(OH),D3 have been identified in the intestine, in kidney, and
in bone (Haussler, 1386, Norman, 1979.1984,1985; W-alters. 1985). More recently.
the 1.25iUHr2rJ, receptor has aiso beer, foilnd in skin, brain, pancreas, pituitary,
and gonadal tissue as well as in a number of cancer cell lines. Presence of receptors
in this wide variety of target cells raises the suspicion that the vitamin D endocrine system has additional, as yet unidentified functions. One such function implicated in the regulation of the immune system has been reported by Rigby (1988).
This should perhaps come as no surprise in view of the common stem cell origins
of bone and immune cells and their shared response to several cytokines. Recent
cloning experiments have shown that the 1,25(OH),D, receptors of both humans
and birds are members ofa family of receptors that also includes those for estrogen,
progesterone, glucocorticoid, thyroxin, aldosterone, and retinoic acid (Minghetti
and Norman, 1988).
The range of functions of the vitamin D endocrine system is now known to
include besides the intestinal, kidney, and bone elements of calcium homeostasis,
regulation of the differentiation of epidermal and hemopoietic cells, and of insulin
secretion. Also, i t plays a role in oncogene expression (Nemere and Norman, 1982;
Reichel e t al., 1989).
In the intestine, 1,25(OH),D, regulates calcium absorption by two different
mechanisms (see Fig. 4). One mechanism is very rapid, occurring over a time span

Osteoporosis: Causes and Treatment

Stinil

BRUSH

159

MUCOSAL CELL

LUMEN

lK

111

FACILITATED
DIFFUSION

INTRACELLULAR
MOVEMENT

ACTIVE TRANSPORT

Active transport
+ionic diffusion

Mitochondrial
binding

Energy dependent

Fig. 4. Intestinal calcium absorption as mediated by 1,25(OH),D, (from Norman, 1990).

of minutes. The other involves gene transcription and is slower, taking place over
a period of hours to days. The latter is the major mechanism; it involves direct
interaction of the hormone-receptor complex with nuclear DNA resulting in production of messenger RNA that codes for proteins involved in intestinal absorption
of calcium. One such calcium-building protein (CABP), calbindin-D,,, (Wasserman and Taylor, 1966) is found in the intestine in concentrations that increase
proportionally with the rate of calcium absorption and in inverse proportion to the
amount of calcium present m the intestine (Christakos et al., 1979; Wasserzliail
and Taylor, 19681.
The cytosol of intestinal mucosal cells involved in the absorption of calcium
contains receptors that are highly specific for 1,25(OH),D,. Their specificity is so
well defined that they bind 1,000 times more tightly to 1,25(0H),D, than to the
intermediate 25-hydroxyvitamin D,. No binding at all takes place with the parent
vitamin D (Norman, 1990). The receptor-1,25(OH),D3 complex transits the nuclear
membrane and interacts directly with DNA. When blood calcium levels are low,
the localization of 1,25(OH),D, in the chromatin is maximal a t 2-3 hours after
entering the cell. Production of messenger DNA reaches maximal levels 2-3 hours
later and calcium absorption peaks 6 hours after maximal RNA production. The
sequence of events can be sustained as long a s low serum calcium levels stimulate
the production of 1,25(0),D,-l-hydroxylase in the kidney. The continued production of 1,25(OH),D, maintains its high serum concentration and continued movement into the cytosol of intestinal mucosal cells. Negative feedback occurs when
blood calcium concentration returns to normal physiological levels.
As mentioned earlier, in addition to the slower, gene-mediated action of
1,25(OH),D,, a rapid increase in calcium absorption with a time course measured
in minutes rather than hours has also been described (Nemere et al., 1987; Nemere
and Norman, 1987; Norman and Ross, 1979; Okamura et al., 1974; Wing et al.,

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1974). This process, called transcaltachia, is thought to involve the interaction of

1,25(OH),D, with the cholesterol component of the target cell membrane in a
manner similar to that known to occur with the antibiotic filipin. Filipins interaction with membrane cholesterol appears to induce the formation of calciumselective pores. In vitro experiments wherein chick intestinal membranes were
treated with filipin induced calcium absorption similar to that induced by
1,25(OH),D, (Wong and Norman, 1975). Transcaltachia does not take place when
blood calcium levels are high. This indicates a negative feedback system that
prevents dangerously high blood calcium levels even in the presence of
1,25(OH),D, in pathologically high concentrations. The mechanisms by which
transcaltachia works are thought to include microtubule reorganization, vesicle
formation, and transport from the lumenal to vascular surfaces of the cell. Transcaltachia is inhibited by the antimicrotubular agent colchicine but is unaffected
Ly d ~ ~ ~ i l W ICIi ll iy B wh:cn suppresses DNA transcription,
THE CELLS THAT FORM, MAINTAIN, AND DESTROY BONE

Adequate intake and absorption of calcium and phosphorus are necessary but
not sufficient to insure calcium homeostasis. A number of factors can cause loss of
calcium from the skeleton even when calcium availability is adequate. The dynamic equilibrium that characterizes the physiology of bone can be upset in a
variety of ways. The specialized cells that are responsible for bone growth (osteoblasts), bone maintenance (osteocytes), and bone resorption (osteoclasts) must all
function in a n intricate pattern of interactions that can be disrupted with pathological effects on bone. The regulation of these interactions involves both local and
humoral factors. The important role played by factors secreted by immune cells in
the regulation of balance between bone formation and resorption is becoming better understood with the availability of purified preparations of products produced
by cells that influence activities of bone cells. Some of the substances that affect
bone remodeling also have the ability to accelerate blood cell production in the
marrow. Substances such as the colony-stimulating factors CSF-G and CSF-GM
are now known to have effects on a number of target cells, the precursors of
osteoclasts among them.

Osteoblasts and osteocytes and bone lining cells

Osteoblasts originate from mesenchyme, undifferentiated cells of mesodermal
origin. Therefore, they share a common origin with cells of the hemopoietic and
immune system (Ortner, 1976, Ustajblaats that reniairi in the iacunae o f hone
continue t u Ftinctjan as osteo
s i ney remain ID comrnunicat?on with t h e vascular system via the endolymph surrounding them in the lacunae and in the
canaliculi t h a t interconnect throughout the lamellae of compact bone. They are
therefore able to participate in the maintenance of serum calcium homeostasis
(Shipman et al., 1985; Stern, 1988). Remodeling of compact bone occurs along the
canaliculi a s well a s along the borders of the marrow cavity. The transition from
the status of osteoblast to that of osteocyte is marked by cessation of alkaline
phosphatase synthesis (Doty, 1981). Within the lacunae, osteocytes are surrounded
by a layer of more-permeable bone, 0.5-2.0 pm thick, that Frost et al. (1960) refers
to as the halo volume. This bone is presumably more readily available for exchange and its presence can only be detected in fresh samples of bone.
The relationship between osteocytes and bone lining cells, whose processes extend into the canaliculi, is a matter of considerable interest. These cells are flat
and in direct apposition to the surface of bone. Their cytoplasm is spread thinly
over bone and their membranes form gap junctions with other bone lining cells as
well as with osteocytes, thus indicating active exchange between cells. Lining cells
are not in direct contact with bone crystals but maintain a narrow seam in which
fluid accumulates (Miller and Jee, 1987; Vanderwell, 1981). While thought not to
participate in bone turnover, these cells may act a s support cells for osteocytes and
act to partition bone extracellular fluid from interstitial fluid. If they play a role
-1

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Osteoporosw Causes and Treatment

161

in resportion, it may be simply one of moving away from areas to be resorbed and
exposing areas of bone to osteoclasts.
Baud and Bolvin (1981) have observed that the level of osteocyte activity seems
to depend upon the cells proximity to more active surfaces of bone. Boyde (1981)
argues that osteocytes themselves are not involved in bone resorption and that
their production of microfilaments and lysosomal vesicles may only be related to
anabolic processes.
Osteoclasts
The major entities of bone modeling, remodeling, and resorption, however, are
the osteoclasts. These cells are of hemopoietic origin, arising from precursor cells
originating in marrow and released into the blood. They are multinuclear, some
having a s many as 50 nuclei. Their formation is the outcome of interaction of bone
marrnw lymphocytes and cells o f the monocyteimacrnphage line The lymphokinw
and cytokines secreted by these cells also appear to activate mature osteoclasts
(Baron et al., 1983; Mundy, 1988). In fact, regulation of the balance between bone
formation and resorption is a t least in part under the control of cells of the immune
system, located in discrete regions of bone. These local factors act in concert with
humoral factors circulating in the blood stream including the several forms of
vitamin D,, parathyroid hormone, and calcitonin (Mundy and Roodman, 1987).
The early stages of osteoclast production appear to be in response to the presence
of Colony-Stimulating Factor (CSF), which is produced by many types of cells.
Although CSF appears to play a n important role in the developmentof osteoclasts
from their precursor cells and their migration (Barnes, 1987) i t does not appear to
stimulate existing osteoclasts to resorb bone. Two types of CSF, one of which
controls macrophage production (CSF-M) and the other which regulates differentiation of the precursors of granulocytes and macrophages (CSF-GM), stimulate
proliferation of osteoclast precursors.
Mundy and Roodman postulate a collection of local factors, produced by lymphocytes, monocytes, and macrophages in the marrow, that promote the next stage of
osteoclast formation. Among these local factors they include interleukin-1, transforming growth factor a (TGF-a), tumor necrosis factor a, and tumor necrosis
factor P (lymphotoxin) (Felix et al., 1989). Osteoclast precursors are attracted to
bone surface, possibly by the presence of osteocalcin (Gla protein). There,
1,25(OH),D3 and parathyroid hormone (PTH) are thought to act synergistically to
cause fusion of precursors forming mature, multinucleated osteoclasts. When they
have achieved this level of maturation, osteoclasts are responsive to lyrnphokines
and cytokines produced by cells in the marrow and will begin the process of resorption. Prostaglandin E,, which is produced by many cells of the monocytemacrophage line as well as by osteoblasts, is also known to have a resorptionstimulating effect (Harvey et al., 1989; Lidor et al., 1989; Stewart and Stern, 1989).
It is thought that neither local factors nor systemic factors act on mature osteoclasts directly. Instead, their presence stimulates a n intermediary which in t u r n
stimulates the osteoclast to begin the process of resorption. At present, the prime
candidate for the role of intermediary is the osteoblast or a n osteoblast precursor
(Meghji et al., 1988). Both categories of cell are known to produce prostaglandin E,,
but their stimulatory effect may be the result of other, a s yet unidentified osteoclast-activating factors (OAF) as well. Parathyroid hormone, cytokines, and
growth factors all have the capability of increasing prostaglandin production while
the antiinflammatory glucocorticoids, 1,25(OH),D,, epinephrine, and estradiol,
can all suppress it, as can nonsteroidal antiinflammatory drugs (NSAID). Other
inhibitors of osteoclastic resorption include calcitonin (CT) produced by the thyroid, while gamma interferon (INF-7) is thought to be a potent inhibitor of osteoclast formation, as is transforming growth factor p (TGF-P).
When activated, osteoclasts resorb bone through a combination of lysosome-like
activity and formation of many low pH compartments alongside the surface of the
bone. This process can be visualized as similar to the placement of a cup upside

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down on the surface of a table. The cup seals off a n area of the surface into which
are secreted protons and lysosomal enzymes. The highly acidic environment created in this compartment dissolves bone mineral, freeing ionic calcium from crystals of calcium hydroxypatite at the surface (de la Piedra et al., 1989; Stepan et al.,
1989a,b).At the same time, lysosomal enzymes digest the organic matrix and other
proteins present in the resorption compartment. The protons secreted into the
compartment may be produced by the action of carbonic anhydrase, which forms
bicarbonate from carbon dioxide and water. The result is the formation of a resorption lacuna with the transient appearance of spicules of unresorbed bone as the
surface erodes.
The movement of protons across the osteoclast membrane is accomplished by two
different pumping mechanisms. One requires the presence of ATP-ase which leads
to the exchange of protons and potassium ions, the same mechanism t h a t produces
stomach acid. It is also possible to simply pump protons into the resorption cavity
as occurs in the kidney. An additional possibility is a n ATP-ase t h a t exchanges
sodium for por;assmm, setting up a n ionic gradient that wouid allow the infiux of
ionic calcium from bone into the resorption cavity (Barnes, 1987).
Once begun, osteoclastic resorption of bone continues for about 10 days and then
stops. Calcitonin can stop it at any time before i t runs its course. But other osteoclasts can mature and become active with the result of sustained resorption under
the appropriate circumstances. Over a period of years, all bone undergoes resorption and turnover is a part of the process of continual remodeling. However, probably no more than 5% of total bone surface is undergoing such turnover at any one
time when the system is in normal equilibrium. Trabecular bone, which constitutes about 20% of total bone mass, has a turnover rate eight times more rapid
than cortical bone because its total exposed surface is much greater (Dodds et al.,
1989; Genant et al., 198913; Kumar and Riggs, 1980). The action of osteoclasts on
cortical bone is limited to the surfaces adjacent to the endosteum and the periosteum and in canaliculi. There is also a general predominance of endosteal over
subperiosteal resorption underlying the remodeling pattern seen in long bones
such a s the metacarpals and radius.

The role of osteoblasts in the remodeling process

Under normal circumstances, bone resorption by osteoclasts has a stimulatory
effect on osteoblasts near the perimeter of the resorption cavity. Osteoblasts arise
from precursors that also may differentiate to produce fibroblasts, chondrocytes, or
adipocytes (Stern, 1987, 1988). Since the mature osteoblast i s active in the synthesis and secretmn of a number of siibatances. it 1s endowed with a large GoIgi
zone and abundant rvugli endopiasrnie reticui1um 1 Wooliand St. John D:xon, 1988;.
Both osteonectin and osteocalcin (Bone-Gla protein) are secreted by osteoblasts
and are used a s markers of bone formation (Azria, 1989; Bar-Shira-Maymon et al.,
1989; Delmas, 1989; Urist, 1986; Wallach, 1989). Collagenase, which degrades
collagen, removing its surface proteins and facilitating osteoclast destruction of
matrix, is also produced by osteoblasts. Alkaline phosphatase, which is a regulator
of the mineralization process, and prostaglandin E, are additional products of
osteoblast synthesis (Azria, 1989; Bar-Shira-Maymon et al., 1989; Harvey and
Bennett, 1988; Nagai, 1989; Rodin et al., 1989; Whyte, 1989).
The primary function of the osteoblasts in bone formation is the synthesis of
collagen. In their earlier stages of development, osteoblasts undergo a process of
development very similar to that undergone by osteoclasts. Their precursors proliferate and migrate to the sites where resorption has occurred. There, they differentiate into mature osteoblasts and are eventually activated to begin producing
collagen and participate in the process of mineralization. It has been estimated
that by the time the mature osteoblast is ready to perform its definitive functions
it is 3 to 4 months past the precursor stage. A number of factors serve to modify the
early stages of osteoblast development. Among the local factors is bone-derived

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growth factor (BDGF), which stimulates a n increase of DNA synthesis of about

50%.
Other local factors influencing osteoblast development are interstitial growth
factor (IGF) and TGF-f3 both originating in bone cells. Cartilage-drived growth
factor (CDGF), produced by cartilage along with IGF also influence osteoblastic
development and activity. It is also believed that factors originating in matrix
have a n effect on the development and activation of osteoblasts. These include
skeletal growth factor (SGF), fibroblast growth factors (FGF), and platelet-derived
growth factor (PDGF). It appears that while a number of factors exert their effects
on all phases of osteoblast activity others have more limited effects. TGF-P, for
instance, stimulates osteoblast replication through mitogenesis but does not appear to play any significant role in increasing collagen synthesis (Canalis, 1984).
In fact, if TGF-P is withdrawn (in vitro r a t calvaria experiments), there is a surge
nf collagen svnthesis which is presumed to be the secondary effect of earlier cell
replication. Besides being produced in matrix, SGF is produced by osteoblasts
themselves, most abundantly by those with the highest alkaline phosphatase levels. When the osteoblast is fully mature, SGF no longer exerts a mitogenic effect
but does increase collagen synthesis. Somatomedin-C, also called insulin-like
growth factor, stimulates development of osteoblasts, especially in the earlier
phases. The long-suspected estrogen receptor has finally been shown to be present
on osteoblasts (Boden et al., 1989; Colston et al., 1989), but the full range of its role
in osteoblastic activity still needs to be determined.
All of the aforementioned growth factors are polypeptides which stimulate mitogenic activity. Prostaglandin E, (PGE2),produced by a number of cells including
osteoblasts can, under the appropriate circumstances, stimulate bone formation
even though its best known effect is on bone resorption. It appears that PGE,
stimulates resorption after chronic exposure, but in low concentrations may have
the effect of stimulating bone formation. At high concentrations, formation is
inhibited and resorption is stimulated by PGE,. One of the key questions to be
resolved if the etiology of osteoporosis is to be fully explained is what links formation and resorption and thereby moderates the range of effects that both local and
systemic factors have on osteoblasts and osteoclasts. As the list of cytokines and
lymphokines known to affect bone cell activity grows, it is increasingly clear that
cellular events well outside the musculoskeletal system have the potential to elicit
side effects affecting bone. The exquisite role played by components of the immune
system in this ever-broadening network of intercellular communication may ultimately prove to be the key to understanding the mechanisms regulating bone
turnover and the events producing disturbances in the dynamic equilibrium of
bone physiology.
Collagen synthesis
When osteoblasts are performing their primary function of bone formation,
whether during growth, modeling, or remodeling of bone, a major aspect of their
activity is collagen synthesis. It is the formation of the collagen matrix that permits the organic framework of bone to be laid down. The type of collagen specific
to bone is designated type I. Its production is regulated at the level of initial
transcription (Raisz and Kream, 1983a,b). It is synthesized a s a single chain, units
of which are linked end to end. These long chains are then wound into a triple
helix. This process, which involves the activity of two enzymes in the presence of
vitamin C, results in the formation of strong cross-linkages involving covalent
bonds. The two enzymes responsible for the conversion of procollagen to mature
collagen are procollagen amino protease, which removes the amino peptides, and
procollagen carboxyl protease, which removes carboxyl peptides. The resultant
modifications allow cross-linkages to occur. It is of interest that one form of osteogenesis imperfecta is thought to be caused by mutations that delay triple helix
formation and allow modifying enzymes to act longer on collagen chains (Brenner
et al., 1990).

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TABLE 2. Products

of

IVol. 33, 1990

osteohlnsts

Collagen I
Osteonectin
Osteocalcin
Proteoglycans I, I1
Alkaline phosphatase
TGF-f3
Sialoproteins I, I1
Prostaglandin

Albanese (1977) notes that both hydroxyproline and hydroxylysine are initially
incorporated in their non-hydrosylated state. With successful modification, crystals form in rod-shaped arrays along the collagen fibrils, which are then laid down
to form sheets. !r. matarc collagcr;, this F I - O ~ U W ~il hrieycomb structure that
facilitates mineralization. Termine et al. (1981) identify osteonectin as a bonespecific protein that links mineral to collagen (see also Robey et al., 1985; Romberg
et al., 1985). The strong affinity of osteonectin to the pro-alpha 1 (I) chain of type
I collagen as well as its strong affinity for hydroxyapatite (Young et al., 1990)
provide the attraction that could serve as the initiator of nucleation. Attachments
of mineral-binding proteins to collagen are at regular intervals that Termine et al.
(1981) refer to as matrix units.
Mineralization
There is disagreement among investigators concerning the degree of spontaneity
inherent in the mineralization process. Vaughan (1981) argues that the process is
initiated by a booster mechanism that raises the calcium or phosphate concentration high enough for spontaneous mineralization of collagen to occur. The mitochondria of osteoblasts accumulate calcium and, under the appropriate stimulus,
allow it to pass into the matrix in sufficient quantity to pass the threshold value
leading to mineralization. Glimcher (1976) argues that spontaneous crystal formation does not occur strictly in response to high concentrations of calcium and
phosphorus. Instead, a catalytic nucleation is accomplished by seeding within collagen. This nucleation would occur around certain nucleation sites that may be the
osteonectin binding sites reported by Termine et al. According to Neuman (1980),
osteoblasts facilitate deposition of crystals of calcium hydroxyapatite as well a s
amorphous calcium phosphates on the organic framework. Mineralization can be
inhibit.ed by limiting the production of seeds iosteonectin?! or by slowing the deposition of mineral on the seeds zlready present. Known inhibitors of mineralization
include pyrophosphate, citrate, and magnesium ions.
Frost and Villanueva (1960) characterized the mineralization process a s a gradual one that produces a region between the end of matrix formation and the onset
of mineralization that they call the osteoid seam, made up of 95% collagen.
Non-collagenous proteins
One of the most impressive aspects of osteoblast activity is the versatility of their
protein synthesis. Table 2 lists the proteins known to be produced by osteoblasts.
Perturbations of synthesis of any of these products have the potential to disrupt
bone formation.
The roles that the noncollagenous proteins play are varied and probably not yet
fully understood. Table 3 lists a number of known and proposed functions.
BONE AS TISSUE

Bone is connective tissue but differs from the other kinds of connective tissue in
having a n important mineral component. The organic component of bone makes up
about 22% of its total mass and water a n additional 9%. The remaining 65-70% is
mineral, predominantly calcium (Triffitt, 1980). The 1,000 to 1,200 g of calcium
stored in the skeleton (Mazess, 1982; Norman, 1980) represents 98% of total body

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TABLE 3 . Functions of noncollagenous proteins

s.ynthesized by osteoblasts'
Regulations of bone mineralization reactions
Signals for cell recognition and attachment
Modulation o f cell differentiation and growth
Determination of matrix organization and
integrity
Modulation of bone resorption and turnover
Markers of bone metabolism
'Following Termine e t al., (1981).

calcium (Eastell et al., 1983; Kimmel, 1984). Most of the calcium in the skeleton is
in the form of calcium hydroxyapatite Clo(P04)6(OH)2,
although a number of other
minerals m a y I epiace calcium 01 arlothek cuiistituerit ir: the hgdruxyapaiitx cryviai
(Posner, 1987). Among the other minerals seen in bone are the fluoride which
replaces the hydroxy ion, carbonate, which replaces phosphate, and magnesium or
strontium, which can both replace calcium. The crystals of hydroxyapatite in recently formed bone differ from those that were formed earlier in t h a t older bone is
made up of larger, more regular crystals with a lower proportion of carbonate
(Bonar et al., 1983; Posner and Betts, 1981; Thompson et al., 1983). Because of the
resultant reduction in surface area, the larger, older crystals are less easily resorbed. Poor mineralization can be caused by genetic disorders (Smith, 1988) that
cause amino acid substitutions in the proteins produced by osteoblasts, including
collagen (Parry and Craig, 1981).
The structure of bone is conventionally designated either as trabecular (cancellous) or cortical (compact). However, under certain circumstances the distinction is
a n artificial one, as when trabecularization of the endosteal surface of a long bone
occurs. About 80% of the human skeleton is compact bone (Polig and Jee, 1987).
Because of its more porous structure trabecular bone is more readily resorbed.
Thirty to 90% of trabecular bone is open space compared to 5% to 30% in compact
bone (Carter and Spengler, 1978). Bone located at the interface of the trabecular
and cortical compartments will often exhibit structural properties of both types
(Kragstrup et al., 1983). Trabecular bone is most abundant in the axial skeleton
which, exclusive of the skull, is 90% trabecular. The appendicular skeleton, on the
other hand, is 95% compact bone by volume (Mazess, 1979). The turnover rate of
trabecular bone is eight times faster than that of cortical bone. About 20% of total
skeletal mass is trabecular, but up to 4 0 5 of the vertebral column is I n that
category !Genant, 19871. Therefore, the effects of perturbations in the balance of'
bone turnover are manifested earliest in the spine. All bone turns over, but only
about 5% of total bone surface is normally exchanged over the course of a year.

Growth, modeling and remodeling

Frost (1983) describes three major processes affecting bone: growth, modeling,
and remodeling. It is the last-mentioned that is of concern here although certain
aspects of growth and modeling, processes generally restricted to the subadult
phase of the life cycle, are of some interest a s well. For instance, the formation of
woven bone, which is the earliest type to appear and which is replaced by lamellar
bone during the 1st year of life (Steinbock, 1976), can be induced by disease or
trauma in the adult. Woven bone is not well organized to cope with mechanical
stresses, but appears to be produced as a n adaptive response to excessive stress and
strain (Burr et al., 1989a,b; Pead e t al., 1988). It is therefore not strictly a pathological phenomenon as claimed by Frost (1988).
When cortical bone replaces woven bone, the lamellae are formed by a process
which aligns collagen fibers so that adjacent sections are oriented in opposite
directions, i.e., either longitudinally or circumferentially. The adjacent lamellae
combine to form Haversian systems of interconnecting lacunae and canaliculi

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Wol. 33, 1990

Fig. 5. Photomicrograph of a section of human cortical bone showing intact Haversion systems (10)and
osteon fragments (FO) (courtesy Sam Stout, 1982).

which are the primary osteons. As remodeling occurs, osteons are destroyed and
replaced by secondary osteons, often leaving portions of some osteons behind (see
Fig. 5). The presence of secondary osteons and the interstitial lamellae that reveal
the occurrence of remodeling form the basis for a system to estimate age at death
through microscopic examination of cortical bone (Frost 1974b,c; Kerley, 1965; Kerley and Ubelaker, 1978). Certain bony features will drift into new positions a s a
result of differential rates of remodeling (Enlow, 1976; Frost, 1985) providing
further evidence of the destruction and replacement of cortical bone. There is
considerable regional variation in the rate af remodeling. For instance, it has been
estimated that a cortex half-life of 7 6 years would be normal for the femur qxhile
a half-life of 24.2 years would be normal in the tibia of the same person. Neither
cortical nor trabecular bone is internally homogeneous. Heterogeneity appears to
be a regional phenomenon (Heaney, 1989a,b).
The remodeling of cortical bone occurs on three bone envelopes: 1)the endosteal,
which is adjacent to the marrow; 2) the subperiosteal, lying under the periosteum
on the external surface of the bone; and 3 ) the Haversian systems within the bone.
A fourth envelope, the trabeculae, will be discussed in the context of trabecular
bone loss (see Fig. 6).

Cortical bone turnover

Under normal circumstances cortical bone turnover is coupled (Frost, 1964;
Jaworski, 1984). The process begins with activation, proceeds to osteoclastic resorption, and finally to reversal and formation of new bone by osteoblasts (Frost,
1980). This process, involving coordination of osteoclasts and osteoblasts, has been
called the basic multicellular unit (BMU) of bone remodeling (Frost, 1973, 1980,
1986). Disturbance of the coordinated activity of the cells making up the BMU can
result in excessive loss of cortical bone, ultimately leading to osteoporosis. When

Stinil
I

Osteoporosis: Causes and Treatment

167

I
LAMELLAR
(LAMINAE)

oR1ENTATKIN

NON-HAVERSIAN

HAVERSlAN
/OSTE-\
PRIMARY
OSTECNS

NON-LAMELLAR

SEcoNabRy
OSTECNS

/
TERTIARY

OSTEONS

\
QWTWAW
OSTEONS

00

Fig. 6 . Sites of internal remodeling showing location o f the subperiosteal, endosteal and interstitial
envelopes and the trabeculae (from Simmons, 1985).

osteoclasts resorb cortical bone, it is usually from sites parallel to the long axis of
the bone in areas where local strains of compression and tension are maximal. The
reversal phase which follows resorption is marked by the presence of mononuclear
cells which are thought to stimulate osteoblasts to begin new bone formation
(Baron et al., 1983). The reversal phase lasts 4 to 6 times as long as the resorption
phase which preceded it. After osteoblasts have deposited new organic matrix
there is a delay of about 8 days before mineralization occurs. I t is, of course crucial
that sufficient calcium be present a t the site of bone formation at this time or the
already completed resorption will not be fully compensated by newly mineralized
bone.
A steady state could be maintained if deposition and resorption occurred a t
equal rates. However, this is not the usual outcome (Johnston and Slemenda,
1987). The most common pattern is one involving loss of bone in the endosteal
envelope with each cycle of remodeling. Most often, the mean depth of erosion
(MDE) exceeds the mean wall thickness (MWT). In other words, the amount of
bone resorbed is greater than the amount formed (Jaworski, 1984; Meunier, 1983).
There is no loss or gain in the intra-cortical envelope although bone quality deteriorates with increasing age, due to the net increase in new bone as opposed to the
more stable old bone. Osteoclasts resorb bone faster than osteoblasts can form it.
Therefore only about one in seven BMUs is in the absorption phase tlnder normal
circumstances (Lee, 1985). Replacement of small segments of bone a t any given
time preserves mechanical integrity of the bone as a unit. Each remodeling event
turns over 0.05-0.1 mm3 per BMU. The result is a pattern of small sections of bone
that have been eroded and refilled at the endosteal surface. In the intracortical
envelope, repeated remodeling results in primary osteons being replaced by secondary osteons and a residue of fragmentary osteons. Osteon replacement also
occurs in the periosteal, endosteal, and trabecular envelopes. However, the periosteal envelope usually experiences a net gain (Parfitt, 1984) with the result that
long bones increase in diameter with increasing age.
Continual remodeling allows replacement of segments of bone where structural
integrity may have become compromised by pathological or traumatic conditions.
It also allows adaptive changes to compensate for new demands. Pressure caused
by such conditions as adjacent aneurysms will lead to resorption (Kelley, 1979).
The presence of marrow tissue appears to stimulate resorption of bone (Frost,
1985). Remodeling is often a response to alterations in the mechanical stresses
generated by activity. Smith (1985) has proposed that osteoblasts act as receptors
for tensile stress. It has also been postulated that mechanical strain can generate
electrical potentials within bone that stimulate remodeling (Lanyon, 1981). Evi-

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[Vol 33,1990

dence for this form of stimulation can be seen in the close association between
areas of high strain and active remodeling sites (Lanyon and Ruben, 1985).El Haj
(1990) cites evidence of a n osteocyte sensor network that transmits information
about stresses and strains through the entire skeletal system.
Fatigue generated by mechanical stress produces microcracks in cortical bone.
These also stimulate repair activity in the appropriate BMUs (Frost, 1985). The
amount of damage done by mechanical stress is largely determined by the type of
loading experienced. Because of its heterogeneous composition, bone is not notable
for its resistance to fatigue damage (Carter et al., 1981a,b). When subjected to
strong compressive forces such a s experienced under weight-bearing conditions,
cortical bone will exhibit shear cracks indicating substantial cellular damage.
Tensile forces, while debonding osteons. do not usually cause cellular damage.
Although primary bone possesses greater tensile strength than Haversian bone
(Vincentelli and Griporov 1985) n+mw lim-it t h e r?xnt?gcby reduciiLg ll:e spread
of cracks which would propagate widely in a more homogeneous material (Currey,
1969). Burr et al. (1985) have shown that the appearance of microcracks is followed
in a few days by a substantial increase in resorptive activity, suggesting that
fatigue damage stimulates Haversian remodeling.
Ninety percent of compressive strength of compact bone is determined by its
density (Mazess, 1982,1987). Consequently, loss of bone mass is directly related to
loss of bone strength which in t u r n is a determinant of fracture risk. However,
compact bone can be remodeled in ways that alter its geometric properties and
stress resistance. For instance, expansion of the circumference of a long bone alters
its cross-sectional moment of inertia (CSMI). The CSMI is closely related to the
bones resistance to bending forces (Burr, 1980; Martin and Burr, 1984). Both mass
and distribution of mass relative to the neutral axis of the bone determine its
resistance to bending. Mass distributed farther from the bones neutral axis makes
a greater contribution to its resistance to bending stress than mass lying close to
the neutral axis. Thus in a long bone with a n approximately cylindrical diaphyses,
bone mineral located on the periosteal surface lends greater resistance to a bending force than bone mineral located on the endosteal surface. Therefore, addition of
bone in the periosteal envelope can compensate for endosteal resorption even
though there is a net loss of bone ova-all (Burr, 1980; Carter and Spengler, 1978;
Martin and Atkinson, 1977; Ruff and Hayes, 1982).
Animal experiments in which equal force is exerted on living bone from all
directions using a centrifuge result in long bones of a circular cross-section (Amtmann, 1971). This is a pattern that would be expected if diaphysial remodeiing
followed a course that would vield maximum resistance tc! the applied bending
stress. Permsteal appositloll at ail points around the diaphyseal circumference
would, under such experimental conditions, maximize the moment of inertia. A
number of investigators are convinced that the geometric properties of bone are as
important in resisting bending stress, and thus minimizing fracture risk, a s is bone
density (Amtmann, 1971; Ruff and Hayes, 1984). According to Burr (1980) and
Sandler (1988), adaptation to loading stress requires adjustments of mass and
geometry although the material properties of bone do not change.

Trabecular bone turnover

Trabecular bone has a much more rapid rate of turnover than cortical bone. The
large surface area presented by the honeycomb-like structure of trabecular bone
makes i t much more available for exchange. Trabecular bone is most abundant in
the bodies of the vertebrae and in the ends of long bones. It is made up of a network
of plates and supporting struts, the strength of which depends upon the density of
its structural components as well a s on the connectedness of the struts and plates
(Merz and Schenk, 1970; Parfitt e t al., 1983; Parfitt, 1984; Weinstein and Hutson,
1987). Although some remodeling of trabecular bone has been reported, producing
radio-opaque lines in response to prolonged stress (Kursunoglu et al., 19881, it is
generally true that when trabecular bone is resorbed, it is not replaced. Thus,

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Osteoporosis: Causes and Treatment

169

TABLE 4 . Qualitative changes in bone

(after Parfitt, 19841
Unrepaired fatigue microdamage
Altered architecture and distribution
Loss of connectivity in trabecular bone
Thinning of cortical bone-porosities
Impaired material properties
Increased brittleness
Molecular disorganization
Defective mineralization

while cortical bone undergoes extensive remodeling over the course of a lifetime,
trabecular bone gradually diminishes in quantity. Heaney (1989aj hypothesizes
that loss of horizontal struts eventually results in the buckling of vertical struts in
what he refers to a s a loss ofconnectedness. Arnold (1981)also reported a n increase
in the distance between vertical struts. As the connectedness of the honeycomb
structure breaks down, the weight-bearing capacity of the trabeculae is compromised and the contribution of the trabecular component to the structural integrity
of the skeleton is also compromised. Thus, in areas that are characterized by a high
proportion of trabecular bone, such as the vertebral bodies, loss of internal support
ultimately leads to a collapse of the cortical shell. One clinical outcome of this type
of trabecular bone loss is the vertebral crush fracture. Another is the femoral neck
fracture occurring in the area of Wards triangle. Early in life, trabecular bone is
the primary reservoir for the maintenance of calcium homeostasis. Being the most
metabolically active component of bone it is also the most vulnerable to perturbations in normal turnover (Jerome, 1989). Therefore, it is generally the first to
exhibit osteopenia (Dodds et al., 1989; Kumar and Riggs, 1980). Trabecular thinning correlates positively with loss of connectedness where loss of load-bearing
capability becomes clinically significant (Compston et al., 1989).
OSTEOPOROSIS: DEFINITIONS AND ETIOLOGIES

The term osteoporosis has come into wide usage to describe conditions in which
bone resorption exceeds bone deposition (Nordin, 1987). Used in this way, its definition overlaps that of osteopenia (Pitt, 1983; Raisz and Johannesson, 1984; Melton, 1989). There is general agreement that osteoporosis is a term to be reserved for
conditions in which there is a reduction of bone mass per volume while the ratio of
mineralized to unmineralized bone is normal (Shane, 1988). This is in contrast to
disorders in which the collagen framework is present with abnormally low levels
of mineralization. This latter condition is referred to as osteomalacia in adults and
rachitis or rickets in children. Raisz (1987) implicates a n element of osteomalacia
in some fractures attributed to osteoporosis in the elderly.
Osteoporosis can affect trabecular bone, cortical bone, or both, depending upon
the stage of the condition observed. Its earliest appearance is generally in trabecular bone but soon both cortical and trabecular bone are involved (Wingate, 1984).
Finally, in the later stages of life, the major area of bone resorption is the cortical
component as the amount of available trabecular bone diminishes. Boskey (1989)
and Lund et al. (1989) report involutional changes in osteoid itself that may inhibit
normal mineralization. In addition, structural changes in calcium hydroxyapatite
have been observed in osteoporotic patients (Lorini et al., 1989). It is evident that
however osteoporosis is defined, it is a disorder of more than a single etiology.
Table 4 lists qualitative changes in bone that can affect its structural integrity.

Type I osteoporosis
Riggs and Melton (1983) propose a definition distinguishing two distinct syndromes. The first (type I) is the form associated with menopause in women. Bone
loss in this disorder is attributable to increased resorption that is most pronounced
in the trabecular component. Because of the high proportion of trabecular bone in

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1Vol. 33, 1990

the vertebrae, type I osteoporosis is associated with vertebral crush fractures (Elders e t al., 1988; Meltzer et al., 1989). Collapse of the vertebral body may be
symmetrical or may occur as wedging with the ventral (anterior) aspect of the
cortex collapsing while the dorsal aspect remains intact. The eighth thoracic to the
third lumbar vertebrae are most commonly involved with T-12 often being the first
affected (Woolf and St. John Dixon, 1988). The result may be a dorsal kyphosis
commonly called the Dowagers Hump. The obligate curvature of the spine and
the loss of stature associated with this condition reduce the volume of the pulmonary and abdominal cavities. If the condition is sufficiently severe, i t can lead to
respiratory and digestive problems of considerable potential severity (Gozzo et al.,
1989; Hodkinson, 1989; Kleerekoper et al., 1989; Shane, 1988).
The distal end of the radius is another area with a large proportion of trabecular
bone (60%). It is the site where the Colles fracture occurs. The occurrence of this
fracture is therefore widely accepted as a n indicator of type I osteoporosis. This
association has been challenged on the hasis of the hi$ propsrti*-rIi.jf I&+-impact
fdis associated with Colles fractures, therefore invalidating its status as a nontraumatic fracture (Aitken, 1984; Riggs and Melton, 1986). However, the rarity of
Colles fractures in forearms of normal density argues for its inclusion a s a n indicator of type I osteoporosis (Eastell et al., 1989). Accelerated bone loss in the distal
forearm has also been reported by other investigators (Price et al., 1989).
Vertebral crush fractures also occur in men (Frances e t al., 1989; Meunier et al.,
1989). Meier et al. (1984) and Orwall e t al. (1990) found that vertebral bone loss in
males was far greater than that seen in the radius (2.3% vs. l%iyr). They found no
correlation between rate of bone loss and age in their sample. But the rate of loss
observed in their longitudinal study exceeded that which would be predicted on the
basis of cross-sectional data. The time of onset of bone loss in males appears to vary
widely and may reflect the degree of fitness. Castration in men is followed by bone
loss (Stepan et al., 1989a).Without a threshold event such as ovarian failure to use
a s a baseline for comparison, studies of bone loss in males have been more inconclusive than those focused on females to date. However, the increasing incidence of
fractures in men reported by Orwall et al. (1990) points up the need for awareness
of the problem of bone loss in both sexes.
It is thought that peak bone mass is attained in women by the midSOs, a little
later in men. However, the vertebral bodies achieve peak mass earlier, a t about
age 25 years. From the age of peak bone mass, there may be a period of perhaps 20
years of relative stability followed by decline. The relatively rapid bone loss experienced by women after menopause continues for a limited amount of time: Riggs
and Melton (1986) estimate 5 to 8 years Although ihe depth of resorption cavrties
formed by osteoclasts generally dPdines with increasing age. there :s a period in
perimenopausai wonien during tihich absorption cavities are deeper. This time of
increased resorption may coincide with a period of reduced bone formation to
produce the accelerated bone loss characteristic of type I osteoporosis (Riggs and
Melton, 1986). Schaadt and Bohr (1988) present evidence that loss of trabecular
bone in the vertebrae occurs during menopause while loss from the femoral neck is
linear through adult life. Loss of compact bone from the femoral shaft is much
later.
Type I osteoporosis involves cortical as well a s trabecular bone loss. One aspect
of the process is the trabecularization of cortical bone through absorption cavity
formation on the endosteal surface of the cortex (Keshawarz and Recker, 1984;
Wahner et al., 1984). The newly trabecularized bone presents a larger surface area
than either cortical bone or older trabecular bone and is therefore highly susceptible to resorption. Moreover, there is also a decline in microfracture repair. The
result is a more easily broken bone (Frost, 1980,1988,1989). A slowdown in bone
turnover may also contribute to bone brittleness by allowing areas of hypermineralization to form (Parfitt, 1987).
As should be evident from the foregoing, the mechanisms underlying type I
osteoporosis, although more often of clinical significance in females, occur in both

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sexes (Nilas and Christianson, 1987). The predominance of trabecular bone loss
and vertebral crush fractures are the usual criteria defining type I osteoporosis.
However, some trabecular bone loss continues well after the postmenopausal period of accelerated involution has ended. Thus, there is considerable overlap in the
symptoms used to designate type I and those used to designate type I1 (senile)
osteoporosis (Johnston and Slemenda, 1987).
Type 11 osteoporosis
Type I1 osteoporosis is usually associated with non-traumatic hip fractures.
However, the most-frequent site of hip fracture occurrence is in an area that
contains considerable trabecular bone (Wards triangle on the femoral neck). One
group of researchers (Mizrahi et al., 1984) found that the density of the trabecular
core of the femoral neck is the chief determinant of its strength. The compressive
strength of trabecular bone is proportional to the square of its density (Carter and
Hayes, 1976). Thus a decrease of density by a iactor of Z wlii resuit in a decrease
in strength of a factor of 4. However, structural factors including the geometric
characteristics of the femoral neck also affect the strength of the bone under stress
(Beck et al., 1990).
Despite the fact that the fracture most often cited as associated with type I1
osteoporosis may be the result of loss of trabecular bone, most investigators view
type I1 osteoporosis as an extended process of cortical bone loss. Both males and
females will experience erosion of cortical bone if they live long enough, and castrated males may experience early bone loss (Stepan et al., 1989a). But the
process generally begins earlier in women, is accelerated for a time after menopause, and becomes clinically significant earlier in women partly because they
have less bone than men at peak bone mass. Since much of the more labile trabecular bone has been lost by the seventh decade of life, the impact of bone loss will
fall most heavily on the compact bone of the skeleton thereafter. The differential
rate of loss in the axial and appendicular skeleton is informative in that it closely
parallels the ratio of trabecular to compact bone. For instance, the decrease in the
female lumbar spine averages 47% through the adult years. The loss averages 58%
for the femoral neck, 39% for the distal radius (which has up t o 60% trabecular
bone), and 30% for the mid radius (which is about 80% compact bone) (Riggs et al.,
1981). The loss is similar in males, but occurs later and because of greater peak
bone mass in males, the net loss is not as likely to result in fractures.
In a longitudinal study of bone mineral loss in old age being conducted in Sun
City, Arizona, the progress of cortical bone loss in the radial diaphysis provides
clear evidence of long bone remodeling which resuits in the thinning of cortical
bone through what Resnick and Greenspan (1989) have described as continued
endosteal resorption. Although continued periosteal deposition of bone appears t o
compensate t o some extent for medullary cavity expansion, it does not appear to be
sufficient to prevent continued declines in bone density in women and, to a lesser
extent, in men (see Tables 5, 6).
To obtain the values shown in Tables 5 and 6, bone mineral content (BMC),
width (WID), and bone mineral density (BMD) were all measured by single photon
absorptiometry of the shaft of the radius one-third of the distance from its distal t o
its proximal end. The data shown were obtained from 221 women and 119 men who
were scanned annually at least three times. The first three columns (BMC, WID,
and BMD) show the mean values for individuals included in the designated age
categories as of December 1989. The fourth, fifth, and sixth columns show the
average percent change in BMC, WID, and BMD per year experienced by individuals in each age category.
The Sun City data shown in Tables 5 and 6 clearly reveal the sex difference in
the pattern of bone remodeling. In women, although there is a continuous decline
in bone mineral density from age 60 years onward, there is also a continuous
increase in the width of the radius. The remodeling of the radius with the consequent loss of cortical bone is less notable in males. Because the width increase is

YEAKBOOK OF PHYSICAL ANTHROPOLOGY

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IVol 33,1990

TABLE 5 Average values and percent change per year in bone mineral content, uirdth, and density
the radial dsauhysis ( S u n City u'omen measured annually 3 or mow timrsi'
Age group
(years)
4 9
60-64
65-69
70-74
75-79
80-84
85-89
>90

Total

BMC

WID

BMD

%Chn BMC

6
14
41
68
60
24
7

0.876
0.797
0.724
0.688
0.649
0.641
0.618
0.634

1.251
1.284
1.260
1.265
1.254
1.270
1.297
1.354

0.696
0.626
0.578
0.545
0.517
0.504
0.477
0.469

-0.032
--0.157
-i-0.051
-0.941
-0.617
--1.180
--0.381
0.521

BChe WID

+ 0.783

i
1.460
i1.272

+0.527

+ 0.657
+0.572
+ 1.284
+ 1.833

in

LicChe BMD
-0.835
- 1.479
-- 1.084
- 1.403
-1.112
-- 1.625
-1.367
-2.059

221
tiometry (SPA).WID = width of the radial
Fl.3.
'6 ,,,,'"I
"y
chg Mac.:, WiIJ, BhlD =

'BMC = Bone mineral content as measured by si

a1 113 $it,?: RMD = h n w rn;w.ml
change per year observed in each

TABLE 6. Average values and percent change per year in bone mineral content, width, and density in
the radial diaphysis (Sun City men measured an,nually 3 or m,ore times)'
Age group
(years)
60-64
65-69
70-74
75-79
80-84
85-89
>90
Total = 119

BMC

WID

BMD

%ChgBMC

%ChgWID

WhgBMD

2
17
28
46
22
4
0

0.946
1.098
1.038
1.143
1.156
1.021

1.585
1.548
1.467
1.544
1.569
1.583

0.617
0.710
0.707
0.742
0.736
0.644

0.253
+0.253
-0.038
-0.451
-t0.106
-1.036

-1.818
-1.818
+ 0.598
+0.345
-0.139
+ 0.562

+ 2.325
+ 2.325

--0.536
-0.761
f0.291
-1.550

'BMC == Bone mineral content as measured by single-beam photon absorptiometry (SPA); WID = width of the radial
shaft a t the distal 1/3 site; BMD = bone mineral density obtained by dividing BMC by WID; %' chg BMC, WID, BMD =
average percent change per year observed in each age category.

accompanied by a continual decrease in bone density in the women we must conclude that bone is being removed from the endosteal envelope while it is being
added to the periosteal envelope. Failure to compensate fully for endosteal resorption through continued periosteal apposition will have the effect of thinning the
cortex and thereby raising the risk of fracture. Other investigators have observed
similar remodeling in the 2nd metacarpal (Garn and Shaw, 1976; Plato and Norris,
1980; Plato and Purifoy, 1982; Piato et ai., 1982). For a comprehensive review of
the st.udies reporting continuing periostcril apposition at a number of sites, the
reader is directed to two recent articles by Lazenby (1990a,b).
Type I1 osteoporosis is a problem for both sexes and the increase in risk of
clinically significant consequences accelerates beyond age 75 years. Males have
more bone mineral and larger skeletons as children (Roche, 1987). Sexual dimorphism for bone mineral content increases throughout growth and development and
young adulthood (Cantatore e t al., 1989). With the onset of postmenopausal bone
loss in women, this dimorphism further increases (Geusens et al., 1989). Loss of
vertebral bone density in normal women begins before age 30 years (Buchanan et
al., 1989), a t a time when men are still increasing spinal density (Cantatore 1989).
Changes in androgenic steroid levels with increasing age are associated with loss
of bone in both sexes (Nordin et al., 1985; Raisz, 1987; Vermeulen, 1985). The
major concerns arising from this association have generally focused on increasing
risk of hip and spine fracture. However, with increasing number of very old individuals of both sexes, all parts of the skeleton are of interest. While decreased
estrogen levels are associated with bone resorption, hence osteoclastic activity,
androgenic deficiency appears to be associated with decreased bone formation,
indicating reduced osteoblastic activity (Longcope et al., 1985). Thus, bone turnover and remodeling can be affected by increased resorption, decreased formation,
or simultaneous occurrence of both. In the last instance, a period of rapid bone loss,

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Osteoporosis Causes and Treatment

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even in the cortical component, would result. In the Sun City and Tucson longitudinal studies, clear evidence of such episodic acceleration of bone loss has been
found. Since the site measured in these studies has been the distal one-third of the
radius, the mechanism can be seen to be a combination of accelerated endosteal
resorption coupled, in the more advanced ages, with a deceleration of subperiosteal
apposition. In women, the width of the radius increases continually from before age
59 years through the 80s, while bone density decreases. However, the rate of
increase declines sharply and bone density loss exhibits a concomitant increase in
the mid-80s.

Secondary osteoporosis
The foregoing descriptions of type I and type I1 osteoporosis have been concerned
with a broad category often referred to as primary osteoporosis, sometimes also
designated involutional or idiopathic. This category is reserved for age-related loss
ofbone. There are, however, a number of- conditions which wlli lead to bone ioss a t
any age. Such conditions fall under the heading of secondary osteoporosis and may
be associated with a variety of pathological, iatrogenic, and lifestyle-associated
causes (Aitken, 1984; Cooper, 1989; Cummings, 1987; Gordon and Vaughan, 1976;
Melton, 1989; Melton and Riggs, 1983; Shane, 1988). Surgery that alters endocrine
status, such a s removal of the ovaries without estrogen replacement, is a n obvious
example. Persistent infections, by stimulating production of lymphotoxins, interleukin-1, and tumor necrosis factor 01, have the potential of causing bone destruction (Mundy, 1988). Smoking also is associated with increased fracture risk (Hemenway et al., 1988; Pocock et al., 1989; Siemenda et al., 1989).
Iatrogenic causes
Reduction in bone density is associated with medically induced hyperthyroidism
(Ross et al., 1987). In addition, the use of antiinflammatory glucocorticoids are a
well-known risk factor for osteoporosis (Bockman and Weinerman, 1990; Clochon,
1989; Reid, 1989a,b). The activity of these adreno-cortical hormones is the result of
the conversion of cortisone to hydrocortisone (cortisol) in the body. One of the
undesirable side effects of cortisone administration is increased sodium retention.
In order to reduce side effects a number of synthetic analogues have been developed. Among the most widely used of these analogues are prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, paramethasone,
and betamethasone.
All of these analogs have longer biological half-lives than cortisone and cortisol
whose biological half-lives are on the order of 8 to 12 hours. Precinisone, prednisolone, and ~ e t h y ~ p ~ ~have
~ ~ half-lives
~ s o n e o f 12-36 hours and dexamethasone, betamethasone, and paramethasone have half-lives of 36-72 hours. Consequently, while these analogues reduce certain undesirable side effects, their
continued presence can enhance osteopenia activity, presumably resulting from a
secondary hyperparathyroidism (Silve et al., 1989). One structural modification of
prednisolone, deflazacort, is thought to have a reduced effect on calcium absorption, collagen synthesis, and bone metabolism (Avioli, 1987). If such modifications
prove to be effective and less damaging to bone, a valuable therapeutic option will
be available under a wider array of circumstances than heretofore. Of course,
endogenous cortisol production can be a source of bone destruction as well. Biller
et al. (1989) report elevated urinary cortisol levels in bulimics, who are a known
high-risk population. It appears that one of the beneficial effects of cyclosporin is
its inhibition of glucocorticoid effects on bone (Kelly et al., 1989).
In order to avoid the side effects of cortisone, cortisol, and their analogs, considerable use has been made of a large category of nonsteroidal antiinflammatory
drugs (NSAIDs). Each of these medications, although efficacious in specific instances, also carries with i t a risk of side effects. A number of them interfere with
kidney function and may even cause serious kidney damage. Others can cause
either discomfort or damage through interactions with other frequently used med-

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[Vol. 33, 1990

ications and patients must be closely monitored to avoid serious side effects including bleeding ulcers. This problem is especially acute in the older patient in
whom absorption and excretion often take place at a slower rate than in youth and
who is also frequently using several medications. However, since several of the
NSAIDs function to reduce PGE, levels, they have the potential to slow the process
of bone resorption by osteoclasts. The degree to which bone resorption is affected by
one of these NSAIDs (piroxicam) is currently being monitored in a series of clinical
trials being conducted a t the University of Arizona.
Diuretics have the potential of raising the urinary calcium loss and thereby the
risk of osteoporosis and fractures. A number of studies implicate diuretics with
increased hip-fracture incidence (LaCroix et al., 1990; Ray et al., 1989). In patients
afflicted with polydipsia, increased calcium excretion has effects similar to those
noted with diuretic administration (Delva et al., 1989). However, some diuretics
including the frequently prescribed thiazides may actually reduce calcium loss by
increasing its reabsorption in the kidnpy tubules.
Dietary factors
It has long been suspected that high-protein diets reduce bone density. Some of
the earlier inferences were made on the basis of bone densitometry studies of
high-protein consumers such a s Eskimos (Mazess and Mather, 1974) and on comparisons of vegetarians and omnivores (Ellis, 1972; Licata, 1981; Allen, 1982; Hunt
e t al., 1989). Allen et al. (1979) suggest that the consumption of a high-protein diet
inhibits calcium reabsorption in the kidney with a consequent increase in urinary
calcium. Kerstetter and Lindsay (1990) cite strong evidence linking commonly
consumed dietary proteins to the level of urinary calcium and calcium balance a t
typical levels of calcium and phosphorus. When the intake of both calcium and
phosphorus is high, as is the case with a diet containing a substantial proportion
of dairy products, the effect of protein on calcium balance is less pronounced.
Dietary protein increases the glomerular filtration rate and consequently, the
filtered calcium load. Possibly because of the greater acidity of the filtrate and the
generally higher concentration of sulfur related to high-protein diets, the reabsorption of calcium is depressed.
The renal response to calcium intake is rapid, occurring within 4 hours of ingestion, and it appears t h a t calcuria associated with high protein intake is persistent, continuing unabated for at least 45 to 60 days. Therefore the potential for a
sustained negative balance of calcium is significant and the effects on bone density
can be substantial. It has also been suggested that high-salt diets increase calcium
excretion in postmenopausal wonien (Zarkadas et al., 1989). Use of alcohol is
associated with reduced bone density (Crilly and I)eiaquerriere-Richardson,1936;
Cummings, 198.7;Diamond e t al., 19891, primarily through its depressing effect on
bone formation.
Type I diabetes
Type I (early onset) or insulin-dependent diabetes mellitus (IDDM) has also been
shown to have a deleterious effect on bone density. The diminished effect of insulin
on osteoblasts in stimulating bone formation is the most likely mechanism underlying the reduced bone density of early-onset diabetics (Weber e t al., 1990).
Pagets disease
Pagets disease is a viral infection that causes a n acceleration of bone turnover
(Kumar and Riggs, 1980). Because of the rapidity of bone resorption and formation
in this condition, the bone that is present is a disorganized combination of woven
and lamellar bone with poor structural integrity (Basle et al., 1988; Delmas e t al.,
1986; Singer and Mills, 1983; Singer et al., 1978). Pagets disease is most often seen
in adults over age 40 years and may manifest itself a t various levels of severity
from asymptomatic to one of high fracture risk.

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Rheumatoid arthritis
Rheumatoid artihritis, being a n inflammatory condition, stimulates endogenous
production of antiinflammatory glucocorticoids. In addition, cortisone and its analogs are still used to treat rheumatoid arthritis (Reid et al., 1989a,b; Sambrook et
al., 1989). The well-known effects of cortisol on bone density raise t h e possibility of
arthritic patients also becoming osteoporotic. The restriction of movement, altered
gait, and discomfort associated with arthritis can lead to increased tendency to fall
and enhance the fracture risk associated with bone density loss. Abnormal resorption activity can be associated with rheumatoid arthritis and periodontal gum
disease, both conditions which raise prostaglandin levels.
Anorexia nervosa
Anorexia nervosa. with or without the symptoms of bulimia, can lead to osteoporosis through reduction in collagen formation associated with undernutrition
(Savvas et al., 1989). Anorexia in effect amplifies the tendency toward osteoporosis
seen in small, lightly built women in general. When combined with bulimia, the
effect on bone is considerable (Howat et al., 1989; Newman and Halmi, 1989).
Osteogenesis imperfecta
Osteogenesis imperfecta is a condition often referred to brittle-bone disease. In
its most severe form, it results in death in utero. In some individuals there can also
be involvement of the teeth, skin, and sclerae of the eyes (Prockop et al., 1985).
Many forms of osteogenesis imperfecta are produced by mutations in the genes for
the alpha chain of type I procollagen (Beighton, 1988; Smith, 1988). It is believed
that the highly repetitive nature of the amino acid sequence of type I tropocollagen
indicates nucleotide sequences coding for it that are also highly repetitive. Highly
repetitive sequences of DNA are susceptible to extensive recombination during
meiosis and mitosis, making type I tropocollagen a protein of considerable potential variability. From the evidence now available concerning the nature of the
mutant forms of collagen, it appears that mutations t h a t either shorten or
lengthen the polypeptide sequences of tropocollagen units account for the most
significant clinical expressions of the condition. Family studies have revealed a
complex mode of inheritance for these conditions but also have shown a connection
between the inheritance of certain forms of osteogenesis imperfecta and that of
early-onset osteoporosis (Prockop et al., 1985). On the basis of such observations, it
is n o t possible to exclude a genetic predisposition from the list of potential causes
of Osteoporosis (Seeman et al., 1989). One problem that disallows a definitive
statement on the genetic component of osteoporosis susceptibility is the recurring
one of definitions. (Osteoporosis is far from being a unitary phenomenon.
The dentine of the teeth is formed by a biosynthetic pathway similar to that
producing bone matrix. A condition, called dentinogenesis imperfecta, is thought
to arise from abnormalities in collagen cross-linkage during dentine formation. It
is somewhat surprising t h a t osteogenesis imperfecta patients have normal dentine
formation.
Other hereditary factors
A genetic predisposition to osteoporosis associated with small body size is highly
probable even when dietary patterns are normal. This can be seen in the high
correlation of bone densities of women of age 20 years and that of their mothers.
Genetic predisposition to osteoporosis also appears to be associated with racial
affinity. African ancestry seems to confer superior peak bone mass (Luckey et al.,
1989; Mayor et al., 1980) and lower rate of bone loss (Solomon, 1979). Both males
and females of African ancestry have greater muscle mass and total body potassium than individuals of European or Asian derivation. Differences in bone density
remain even after adjusting for body mass (Pollitzer and Anderson, 1989). In their
review of the literature on the heritability of bone mass, Pollitzer and Anderson

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YEARBOOK OF PHYSICAL ANTHROPOLOGY

IVOl. 33, 1990

found considerable evidence of a significant role for hereditary factors in the determination of bone density. However, environmental factors appear to play a n
increasingly important role with age, especially in women. The influence of
changes in body composition and exercise levels appears to have the potential to
offset hereditary determinants of bone density andlor fracture susceptibility in
both sexes. This, of course, should not be surprising in view of the dynamic nature
of bone throughout life.
Reproductive history
Whether childbearing has the effect of reducing bone density is a question of
considerable interest. On the one hand, late onset of menarche and childlessness
appear to be associated with low bone densities. On the other hand. the divwqion
of calcium 60 the letus constitutes a substantial demand on the maternal calciuni
reserves, especially when calcium intake is low. The skeleton of the human newborn contains 25 to 30 g of calcium, 80% of which accumulates during the final
trimester of gestation. Often, however, the mothers skeleton also increases its
total mineral content at the same time. Alterations in maternal levels of parathyroid hormone, calcitonin, and serum calcium have all been reported (Galloway,
1988). The net result is increased absorptive efficiency during pregnancy. If sufficient calcium is present in the diet, a positive calcium balance is maintained. Since
lactation creates a n extended demand on maternal reserves, this positive balance
is essential to avoid later bone loss.
In Galloways retrospective study of postmenopausal women, number of children
and total months of lactation were compared to bone densities (at the distal onethird site of the left radius). Women who had had children were clearly a t a n
advantage in terms of bone density when compared to nulliparous women. Having
pregnancies in the teens and 20s appeared to produce the greatest enhancement in
bone densities in this study. The total length of time a woman spent lactating over
all of her childbearing years has a modest negative effect on bone density values.
With respect to the length of lactation following each pregnancy, there appears to
be a n adverse effect on bone density associated with greater duration of lactation.
Women who continued breast feeding for more than 6 months per full-term pregnancy exhibited lower values in postmenopausal bone density than those who
breast fed for a shorter time. Short interbirth intervals followed by longer periods
of breastfeeding were associated with lower postmenopausal bone densities, a finding that may indicate excessive demands on maternai calcium reserves during the
reproductive yea
Alsoz since tlic intake of caicmm probably did nut increase
substantially in
population during the childbearing years, they probably were
unable to capitalize on the increased efficiency in calcium absorption that accompanies pregnancy. Therefore, women who experience frequent pregnancies followed by extended periods of breast feeding may, with sufficient calcium intake, be
able to satisfy their own needs a s well as those of the fetus and infant, but the
length of time that calcium balance can be so maintained is probably limited.
Wardlaw and Pike (1986) have shown that long-term lactation results in reduced
bone mass with the reduction being especially notable in the trabecular envelope.
However, when women received the recommended daily allowance for calcium
regularly, Koetting and Wardlaw (1988) were able to find no increase in risk of
osteoporosis even in cases of prolonged lactation.
In cases of repeated early pregnancies coupled with extended periods of lactation
without assurance of adequate calcium intake, risk of bone mass is maximized.
This, of course, is not a n uncommon set of conditions on a worldwide basis. It is one
in which the attainment of peak bone mass would be delayed and ultimately,
attenuated. Since peak bone mass is a n important determinant of later tendencies
toward osteoporosis, measures to ameliorate the enhancement of fracture risk in
later life might well be concentrated in the years preceding attainment of peak
bone mass.

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Early attainment of peak bone mass

Many researchers and clinicians are convinced that the only effective way to
reduce the incidence of osteoporosis in a steadily aging population is through
preventive measures. One such measure is the encouragement of nutritional and
lifestyle patterns that maximize peak bone mass. Accordingly, considerable emphasis is being placed on calcium intakes and exercise regimes for the years when
the skeleton is growing most rapidly and acquiring the adult mass. One investigator (McCulloch,1989)cites evidence that the greatest impact on peak bone mass
is derived from sports activities engaged in childhood. However, Lloyd et al. (1988)
show that adolescent athletic activity sufficiently strenuous to induce amenorrhea
can cause reduced peak bone mass. Others, such as Haliova and Anderson (1989)
cite evidence that lifetime attention to calcium intake is important but not sufficient to achieve ideal peak bone mass without appropriate exercise. Gilsanz et al.
i l 9 8 X ) otter evidence that the amainrriarit u f p t ~ h
driiaity in the trabecular bcnc ef
the vertebra occurs in the late teens or early 20s in women and that the onset of
trabecular bone loss occurs in the early 20s. When the trabecular bone of the
calcaneous is monitored, it appears that loss does not occur until the mid-30s and
that 80% of a sample of women aged 20 to 35 years enrolled in a regular running
program either maintained or increased bone mass over the course of a years
study. Matkovic et al. (1987) argue that on the basis of their observations, the need
for skeletal calcium is highest from 10 to 20 years of age and that insufficient
calcium intake during these years can predispose to osteoporosis later in life.
Heaney (1988) and Heaney and Recker (1987) also urge measures that maximize
peak bone mass in the crucial formative years before age 20 years.
Exercise and maintenance of bone mass
Although there is general consensus that nutrition and exercise are both important components in the attainment of a skeletal mass sufficient to minimize fracture risk in later life, there is less agreement on the effectiveness of exercise in
maintaining bone mass in adulthood. There is a substantial body of evidence that
both lack of mechanical strain and excessive strain are destructive to bone (Frost,
1987a). Bed rest has long been known to produce disuse osteoporosis (Stout, 1982,
Unthoff and Jaworski, 1978; Vico et al., 1987). Men living in nursing homes have
significantly lower bone density than age-matched men living in surrounding communities (Nagraj et al., 1990). The weightlessness of space travel has produced
clear evidence nf bone resorption and increased urinary excretion of calcium in
young. fit individuals in a relative short length of time. Rambaut (19871summarizes some of the evidence collected as part ofthe U.S. and Soviet space programs.
During the Gemini flights, loss of bone density in the calcaneous ranged from 2.9%
to 15.1% in flights of 4, 8, and 14 days duration. In the Apollo program, 5 of the 6
astronauts experienced bone loss in the vertebrae as well as in the upper and lower
limbs. After Apollo 17, a voyage lasting 12.6 days, increases in urinary and fecal
calcium as well as disturbance of intestinal absorption of calcium were observed. A
loss of 0.2% of total skeletal mass was estimated. In the Skylab program, bone loss
increased after the 1st day of weightlessness and attained a level of 200 mg per day
after 2 months in space. During 84 days in space the average individual loss was
25 g of calcium. The effects of weightlessness seemed to be most pronounced in
weightbearing bones as indicated by the fact that the greatest loss occurred in the
calcaneus. Along with increased urinary excretion of calcium, there was an increase in hydroxyproline indicating resorption of the collagen matrix of bone.
Urinary cortisone excretion was also 20% to 100% above preflight levels in these
individuals.
Weightlessness, inactivity, and restriction of movement all have the effect of
producing bone loss through remodeling in the adult. Of course, the early stages of
development of the human skeleton in utero take place in a hypogravic environment. At this stage, bone growth and modeling take place according to a genetic

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program with little or no environmental input (Jaworski, 1987).In the adult, bone
is highly responsive to the environment with the result t h a t the skeleton is in a
constant stage of remodeling.
The well-documented negative effects of inactivity have led to attempts to maintain or increase bone mass through exercise programs. There are published reports
of hypertrophy of bone under appropriate conditions such a s in the dominant arm
of tennis players (Jones e t al., 1977; Smith e t al., 1984). However, the degree to
which beneficial effects can be produced by exercise remains uncertain. On the one
hand, a number of investigators report a prophylactic effect of exercise on bone loss
(Jacobson e t al., 1984; Krolncr et al., 1983; Smith et al., 1989a,b; Talmage et al.,
1986). On the other hand, Cavanaugh and Cann (1988) found no beneficial effect
associated with a regular walking program and Johnell and Nilsson (1984) found
no correlation between bone mineral content and exercise in a sample of perimenopausal women. There does seem to be an association between the amount of exercise and it. effect on hone de3siiy !M?IIRUC. 1957: M2rc12s and Ca;.tcr :953:,
Williams et al. (19841 found that while there was no discernible improvement in
the bone mineral content of short-distance or occasional runners, increased bone
mineral content was seen in consistent long-distance runners. Chow et al. (1987)
and Dalsky et al. (1986) both observed significant positive effects of endurance
exercise on bone mineral in post-menopausal women. Kirk et al. (1989) and Leichter et al. (1989) report similar findings when exercise is strenuous or of the endurance category.
While exercise may have beneficial effects on bone mass, exercise of sufficient
intensity to produce amenorrhea has the effect of reducing bone mineral content in
young women (Drinkwater, 1987; Drinkwater et al., 1984, 1990). High training
intensity in female athletes causes a reduction in serum estrogen levels which has
the effect of reducing bone formation as well as producing amenorrhea (Baker and
Demers, 1988; Lutter, 1983). Ding et al. (1988) have detected high serum cortisol
levels in amenorrheic athletes, a factor which may contribute to the high bone
turnover rates seen in athletes of both sexes (Nishiyama e t al., 19881, along with
the effect of the high strain levels noted by Burr et al. (1989a,b). Lindberg et al.
(1987) report a n increase in vertebral bone mass following a reduction in activity
levels in amenorrheic runners, indicating that the reduction in bone density is a t
least in part reversible when estrogen levels return to normal.
Exercise, even though of potential benefit in the maintenance of bone mass, may
increase the risk of a fracture-inducing fall. The growing concern about increased
incidence of osteoporosis is in large part focused on the increased risk of fractures
and their scguelae. The increase in morbidity and mortality in older fi-acture
oporasis that has created a
ct
patients lend.; an element o f lethality
urgency to the search for a better understa ng of the etiology of the con
well a s a n intensified interest in the nature of fracture-producing accidents and
ways of preventing them (Campbell et al., 1989). The fractures usually associated
with osteoporosis include Colles fracture of the wrist, vertebral crush fractures,
and fracture of the femoral neck. However, loss of bone is not by any means limited
to these areas. The ribs, pelvis, and scapulae all undergo considerable resorptive
loss and, in the very old, a slight accident is often the cause of multiple fractures.
Cummings and Nevitt (1989) hypothesize a set of conditions t h a t potentiate one of
the most dangerous fractures, the hip fracture, in older people. Implicated in the
increased risk of fracture with increasing age and loss of muscular coordination
with a lack of exercise are a series of neurological and neuromuscular changes that
not only increase the likelihood of falling but also reduce the ability to effect a n
appropriate protective response. Loss of soft tissues with increasing age has the
effect of removing a soft-tissue cushion from the point of impact and the change in
habitual gait increases the likelihood that a fall will produce a n impact directly on
the hip joint. When these factors combine with a severely reduced bone mass in the
femoral neck the likelihood of a fracture is high. With a mortality rate in excess of
10% within a year of such fractures, it is not surprising that the prospect of a fall

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is severely frightening to most older people with the result that their mobility is
greatly restricted, especially in areas of winter snow and ice. Fear of falling is
rightly shared by both sexes in advanced old age.
TREATMENTS

Estrogen replacement therapy

To date, the most successful treatment for the prevention of osteoporosis in
women has been estrogen replacement therapy (ERT) (Bush et al., 1983; Ettinger,
1988; Genant et al., 1989a,b; Mazess e t al., 1989; Quigley et al., 1987). Treatment
has been successful in young, hypoestrogenic women experiencing primary ovarian failure as well as in older women (Louis et al., 1989). Both oral and transdermal (Adami et al., 1989; Riis et al., 1987) modes of administration have been
effective. The combination of estrogen and progestogen is now widely prescribed
for postmenopausal women to reduce the risk of endometrial hyperplasia (Isaia et
al., 1989; Munk-Jensen et ai., 1988).Notelovitz (1987; &ims th3t estrogenq will
stop bone loss no matter when or how long they are administered. However, the
earlier in the perimenopausal period ERT is started, the more effective i t is in
retarding bone loss. Treatment should at any rate, begin within 3 years of menopause. Progestins appear to have antiresorptive effects of their own that may
derive from competition for glucocorticoid receptors. However, long-term oral contraceptive use appears to have no effect, either positive or negative, on trabecular
bone (Lloyd et al., 1989). One drawback of ERT is that withdrawal of estrogen is
followed by a profound and consistent loss of bone (Notelovitz, 1987). Ettinger e t al.
(1987) have found that a combination of a low dosage of estrogen and calcium
supplementation is effective in preventing postmenopausal bone loss. The effect of
ERT appears to be primarily on the trabecular envelope with major benefits being
seen in the vertebral trabeculae (Hosie et al., 1989).
Anabolic steroids
Another hormone treatment that is the subject of several ongoing clinical trials
is the use of anabolic steroids (Gennari et al., 1989; Hassager et al., 1989; Johansen
et al., 1989; Need et al., 1989a,b). One compound that is currently being widely
tested is nandrolone decanoate, which may have beneficial effects on b.oth trabeca l a r and cortical bone.
Growth hormone
In a recent study of the effects of growth hormone replacement in men over age
60 years (Rudman et al.. 19903, it was found that increases in both muscle mass
and bone density of the iumbar vertebrae could be induced by administration of
physiological levels of biosynthetic human growth hormone for 6 months. In addition to the effects on muscle mass and bone density, growth hormone induced a
reduction and redistribution of fat deposits and thickening of the skin.
Calcitonin
In some cases of osteoporosis, there is evidence of slow bone turnover, with little
activity on the part of the osteoblasts but sufficient osteoclastic activity to produce
a net loss of bone mass. In other cases there is evidence of high activity in both bone
formation and bone resorption, with resorption outpacing formation to produce a
net loss of bone mass. The latter (high turnover) form of osteoporosis lends itself to
treatment with calcitonin. Calcitonin is a highly potent inhibitor of bone resorption (Wallach, 1987). Whether it has any effect on bone formation is unclear.
Several investigators have reported beneficial effects in long-term treatment of
osteoporosis with calcitonin or combinations of calcitonin, calcium supplement,
and vitamin D (Gennari and Avioli, 1987; Resch et al., 1989). The greatest effect
of calcitonin treatment is seen in trabecular bone. Whereas Wallach measured
total body calcium increases of from 2% to 4% in responsive patients, dual photon
absorptiometry of the spine showed increases of from 9% to 20%. Even in successful

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clinical trials of calcitonin, nonresponders are as frequent as responders, possibly

reflecting the ratio of low-turnover to high-turnover osteoporotics in the subject
sample. Calcitonin also has a n analgesic effect that appears to provide some relief
to patients even when bone mass values show no improvement. Monkey experiments have shown a rise in endorphin levels stimulated by calcitonin, which is a
neuropeptide, but the origin of the analgesic effect in humans has not been determined. Although it appears that calcitonin has a place in the treatment of some
types of osteoporosis, its efficacy appears limited. Moreover, recent studies have
shown that calcitonin levels are no lower than normal in osteoporotic women
(Prince et al., 1989), so effective administration requires pharmacological, not
physiological dosages, and the nature of long-term side effects is still to be determined.

Vitamin D
The effectiveness of vitamin D therapy in the treatment of osteoporosis is a
controversial topic. Although there is no question that 1,25(OH),D, is a n important factor in the asorption of calcium in the intestine, a deficiency in serum
vitamin D levels is not always a concomitant of osteoporosis (Gallagher et al.,
1980). However, there is a segment of the osteoporotic population t h a t exhibits
poor calcium absorption even when values are age-adjusted and in some of these
cases fecal calcium has been found to exceed calcium intake (Gallagher et al., 1979;
Riggs et al., 1982). Gallagher (1987) cites a number of studies in the United States
and in Europe which report increases in spinal bone density following treatment
with vitamin D, or one of its analogues. Increased density in the radius was also
recorded indicating that the effects of this therapy extend to cortical as well as
trabecular bone. While the primary effect of vitamin D seems to be improved
calcium absorption, Gallagher cites evidence that there may be a n enhancement of
bone formation as well. If this is indeed the case, vitamin D therapy may be the
treatment of choice in low turnover osteoporosis whereas calcitonin would be selected where high-turnover osteoporosis was diagnosed. Despite some encouraging
results, the efficacy of vitamin D therapy remains in doubt. Wronsky et al. (1986),
for instance, report t h a t although chronic administration of 1,25(OH),D, appears
to increase bone formation, it can also decrease mineralization. Ott and Chestnut
(1989) simply report t h a t calcitricol treatment is not effective in postmenopausal
osteoporosis. Part of the problem encountered in establishing the value of vitamin
D, calcitonin, calcium supplementation, and steroids in the treatment of osteoporosis is that they interact with each other as well as with local factors which in turn
are inf1uc.ncc.d by cytokines produced by a wide range of cells. The complexity nf
the system makes it unlikely that any slngie treatment will yield consistently
favorable results.

D iphosphanates
Oral diphosphanate compounds have been used for a number of years to reduce
the loss of bone mass occurring in Pagets disease (Guncaga et al., 1974; Fleisch,
1981, 1987). Their success led other investigators to apply similar methods to the
treatment of postmenopausal osteoporosis (Heaney and Saville, 1976; Valkema et
al., 1988; Watts et al., 1990).
A treatment regime involving sequential stimulation and depression of osteoclastic activity, called coherence therapy (Frost, 19791, was developed and successfully applied by clinicians striving to slow or arrest the loss of bone associated
with postmenopausal osteoporosis (Anderson et al., 1984). The underlying premise
of coherence therapy is that by alternating periods of stimulation of osteoclast
activity by increasing serum concentrations of phosphorus or parathyroid hormone
with periods of suppression of osteoclast activity by a biphosphate such as etidronate, it is possible to synchronize bone resorption and formation. At intervals, the
treatment is stopped permitting osteoblasts to form new bone unhindered. By
repeating such cycles i t is possible to effect a net gain in bone mass (Frost, 1979;

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Mallette e t al., 1989). The successful application of coherence therapy by Anderson

et al. involved administration of phosphorus for 3 days. This was followed by
administration of 5 mg etidronate per kg body weight per day for 15 days. Then, a
medication free period of 10 weeks was maintained. The entire cycle was repeated
for 9 to 24 months. The result was a marked improvement in bone mass. Other
investigators reported less success in applying the same method (Pacifici et al.,
1988), possibly due to poorer absorption of etidronate. As a rule, only 1%to 9% of
a dose of etidronate is actually absorbed. Absorption is dose dependent, being 1%
at 5 mgikg, rising to 2.5% a t 10 mgikg and 6% a t 20 mgikg. Calcium and dairy
products interfere with etidronate absorption (Fleisch, 1987; Fogelman et al.,
1986) making it necessary to require that administration occur only with water at
the midpoint of a 4-hour fast. Etidronate is not metabolized. The portion that is
absorbed is either adsorbed to bone or eventually excreted in the urine. The unadsorbed portion is excreted intact in the feces. Adsorption to bone is most avid in
areas of active ost,eogenesis. it inhibits the *.formation: growth, and dissolution or
calcium hydroxyapatite crystals and their amorphous precursors by chemisorption
to calcium phosphate surface (Barnhart, 1988). It may retard mineralization of
osteoid that has already been laid down. This osteoid apparently mineralizes normally later as a phase of the mechanism exploited by coherence therapy.
A recent study (Storm et al., 1990) has shown that the biphosphanate etidronate
significantly lowers the rate of bone turnover and fracture occurrence in women
with postmenopausal osteoporosis. In this study, 33 women were treated with
etidronate and another 33 were given a placebo. All of the women were followed for
150 weeks. In the treatment group, a significant reduction in bone turnover compared to baseline level was observed after 60 weeks of treatment. After 150 weeks
of treatment, turnover rates had returned to slightly below baseline levels. In the
control group, no reduction in turnover was observed after 60 weeks, but the rate
of turnover was significantly increased after 150 weeks. Other investigators have
also reported success in treatment with etidronate (Genant e t al., 1987; Hodsman,
1989). Calcitonin intervention has been shown to produce a similar sequence of
bone mass increase followed by a plateau (Gruber e t al., 1984; Gennari et al., 1985;
Mazzuoli et al., 1986).
The occurrence of a plateau may be produced by a mechanism postulated by
Parfitt (19801,in which a n increase in bone mineral content is the result of reduced
remodeling. Resorption cavities are filled in until there are no more left to fill. At
that point, no further increase will be seen. An additional factor that could explain
the observation of higher bone mineral content is that a reduced rate of turnover
results in a n increase in the mean age of the remaining bone. Older bone is more
heavily mineralized, so the result is a net increase in bone mineral content.

Fluorides
The ability of fluoride to replace hydroxy units in the calcium hydroxyapatite
crystal, yielding a more-stable calcium fluorapatite, has been recognized for many
years. Therefore, the use of fluoride to arrest the progress of osteoporosis has
attractive possibilities. The results of several studies using sodium fluoride in
already-diagnosed cases of osteoporosis have been encouraging (Lundy e t al., 1989;
Pak et al., 1989; Riggs e t al., 1990). The most consistent success has been in
treatment of vertebral bone loss, often in conjunction with calcium supplementation (Farley et al., 1989; Heaney et al., 1989a-c; Hodsman and Drost, 1989;
Mamelle et al., 1988). Kragstrup et al. (1989) have had success using a combination of sodium fluoride, vitamin D, and calcium. Meunier e t al. (1989) report
increased density of the spine in drinkers of mineral water rich in fluoride. While
the beneficial effects of fluoride on the retention of trabecular bone are encouraging, Iledlund and Gallagher (1989) report a n increase in hip fractures in a sample
of osteoporotics being treated with sodium fluoride. Mackie et al. (1989), using a
combination of sodium fluoride, calcium, and vitamin D to treat patients with
femoral neck fractures report improved bone densities. From the range of results

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reported from the use of sodium fluoride, it is again evident that no single treatment will produce universally successful results in a system as complex as that
governing bone metabolism.

Calcium
Perhaps no aspect of the prevention and treatment of osteoporosis is more controversial than the effectiveness of calcium supplementation. The recommended
daily allowance of calcium for estrogen-replete, premenopausal women has been
raised to 1,000 mg (Peck, 1984) and that for postmenopausal women to 1,500 mg
(Barrett-Connor, 1989; Heaney et al., 1989b,c; Recker, 1987). However, a number
of investigators do not support the position that high calcium intake is an assurance of greater bone density (Cummings et al., 1985; Gallagher et al., 1980; Hegsted, 1986). Data from a number of Western countries yields little support for the
contention that bone density is predictable on the basis of calcium intakes (Falch,
1984; Garn et al., 1981; Sowers et al., 1985). Although there is considerable skepticism about the benefits of calcluni Supplementation iater in life, t h e desirability
of sufficient dietary calcium to increase peak bone mass early in life is more
generally accepted (Matkovic et al., 1987; Tylavsky et al., 1989).
Insufficient calcium intake t o maintain homeostasis is always a risk factor for
osteoporosis (Heaney and Recker, 1987; Shane, 1988). Poor absorption can make
even the most generous calcium intake inadequate, especially in older, lactoseintolerant individuals. Considerable attention is currently being given to the bioavailability of calcium supplements. Calcium carbonate, the most widely used
calcium supplement, is not the best absorbed. Calcium citrate and calcium pidolate
are better sources of calcium than calcium carbonate, calcium chloride, calcium
fluoride, calcium gluconate, or calcium phosphate (Bellony et al., 1989; Harvey et
al., 1989). It is generally recommended that calcium supplements be ingested with
or shortly before a meal to improve absorption. It has also been suggested that
calcium supplements taken with the evening meal raise serum calcium levels
during the night when parathyroid hormone secretion is maximal. Reduction in
the amount of parathyroid hormone secreted in the presence of high serum calcium
concentrations would reduce osteoclastic activity and thereby slow the amount of
bone resorption.
Notelovitz (1987) offers three major considerations concerning the value of calcium supplementation: l) calcium is absorbed as efficiently from calcium supplement as from dairy products; 2) the amount of calcium in calcium supplements that
is available for absorption is important; 3) calcium absorption can be enhanced by
the concomitant ingestion of appropriate types of food such as carbohydrate polymers, yogurt, or a full meal.
R e y n d a certain ieve: of intake, iidditionaf
Calcium is a threshold nuirie
amounts become superfluous and perhaps harmful. For this reason, there has been
concern about toxic effects of high daily intakes of calcium. The possibility of stone
formation in the kidneys, ureters, or bladder as a result of sustained high calcium
intakes has been raised (Shah and Belonje, 1988). However, absorption of calcium
is usually so poor that the occurrence of urolithiases has been rare. One caution
should be offered: whenever high calcium intake is sustained, adequate fluid intake is essential, especially in exercisers.
In summary, if there is doubt that the daily requirement for calcium is being
met, supplementation in one form or another is justifiable. Howvever, there is no
guarantee that supplements will be absorbed and, even if calcium is absorbed, that
it will slow bone loss in older adults. Therefore, there is no satisfactory blanket
recommendation that can be made concerning the use of calcium supplements to
prevent or ameliorate osteoporosis.
CONCLUSIONS

Calcium is an element of fundamental importance in a wide range of biological

systems. Homeostatic mechanisms whose function it is to guarantee continual

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Osteoporosis: Causes and Treatment

183

availability of calcium have a high priority commensurate with their crucial importance. Being the ultimate reservoir of calcium, the skeleton must respond to
demands made by other tissues by relinquishing a n essential component of its
structural integrity promptly when needed. The cells that form, maintain, and
destroy bone are highly efficient in their function of allowing bone turnover while
maintaining structural integrity. However, the balance between bone formation
and bone resorption is a precarious one. It can be disturbed by a reduction in
calcium availability, as from insufficient intake or absorption, or excessive excretion. It can also be disturbed by a lack of sufficient activity to sustain a normal
environment of stresses and strains. Any upset in the systemic factors that modulate bone physiology has the potential to tip the balance toward a n excess of
formation or resorption. Thus, alterations in serum levels of parathyroid hormone,
calcitonin, androgenic steroids, vitamin D in its several forms, and glucocorticoids
are all potential sources of altered bone turnover rates.
Local factors, the product of cells and tissues of a wide variety Uf
origin, interact with systemic factors either synergistically or antagonistically. As
a result, the range of responses is wide, with a n almost infinite number of intermediate values being possible when a disturbing stimulus is experienced. The close
affinity of the cells involved in bone turnover with those of the hemopoietic and
immune system results in the occurrence of receptors and cytokines common to all.
Thus, bone responds to more than demands for calcium or the mechanical requirements of the many elements of the musculoskeletal system. I t should not be surprising, then, that perturbations in bone turnover producing pathological consequences generally subsumed under the head of osteoporosis may arise from many
causes and may respond to many treatments under appropriate circumstances.
The variety of treatments described above, each having produced both successes
and failures, is a good indication of the many ways in which the system can be
disturbed. In the absence of a single over-arching mechanism t h a t can be modulated to regulate bone turnover, it is likely that the number of treatment strategies
will continue to grow as more factors capable of perturbing the dynamic equilibrium of bone turnover are identified. Perhaps the most useful new insights will
come from related areas of research, especially in immunology, that cast light on
the language of intercellular communication. Even old bones can heal when broken and, in a very real sense, bone growth is a lifelong process. Although loss of
bone density in old age is generally considered to be a normal occurrence, there is
abundant evidence that it can be modified sufficiently to avoid the risks of osteoporosis. Therefore, despite the rapid increase in numbers of potential victims of
osteoporosis, a n osteoporosis epidemic is by no means inevitable.
This review has attempted to piace the condit,ion of osteoporosis in its full biological context. By examining the physiological role of calcium, it can be seen that
the maintenance of homeostasis is of crucial importance. Extraction of calcium
from food and its retention or excretion are processes of such biological significance
that multiple backup mechanisms are essential.
Bone provides one such mechanism, acting as the ultimate reservoir of calcium.
Its dynamic nature is seen in the level of lifetime activity maintained by osteoblasts, osteocytes, and osteoclasts. Bone turnover involving both trabecular and
cortical components is subject to perturbations from a variety of factors. The process of aging involves changes in bone turnover arising from a number of these
factors. Where the maintenance of structure is incompatible with the maintenance
of homeostasis, structure is altered. The list of factors known to be capable of
inducing bone loss is a lengthy one. Not surprisingly, so is the list of treatments
t h a t have demonstrated at least some degree of efficacy. It is hoped that this
overview will provide the reader with some guidelines for approaching the complex
and burgeoning literature on the condition widely but incorrectly designated osteoporosis.

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