Osteoporosis

    Osteoporosis is a chronic-degenerative and incapacitating condition of generalized skeletal 
fragility due to a reduction in the amount of bone and a disruption of skeletal microarchitecture to 
the point that fracture vulnerability increases.  
    It is a frequent osteometabolic disease, with a high morbidity, frequently associated with 
hip and vertebral fractures.  
    The increase in life expectation, specially in developed countries, is causing a similar 
increase in the prevalence of osteoporosis. It is an age related process, although estrogen 
deficit also play a important role.  
    It is estimated that 50% of osteoporosis femur fractures expand to total or partial incapacity 
and that 20-30% of individuals suffering from osteoporosis femur fractures show thromboembolic, 
circulatory or respiratory complications, leading to death in the following two years after the fracture. 
    The most common types of fractures are vertebral, distal radius (Colle's fracture) and ribs.  
    Bone Remodeling
    Abnormalities in bone reabsorption or formation constitute the final common pathway through 
which diverse causes, such as dietary or hormonal insufficiency, can produce bone loss.  
    Bone turnover is about eight times much faster in the trabecular bone than in cortical one. 
So, the increase in bone turnover that takes place in the menopausal period will lead to a 
bone loss especially in sites that are rich in the trabecular bone. 
    This is the reason why vertebral bones are the primary sites of bone loss in osteoporosis.  
Remodeling is initiated by hormonal or physical signals that cause mononuclear marrow-derived 
precursor cells to cluster on the bone surface, where they fuse into multinucleated osteoclasts, 
with cytoplasm full of mitochondria, free ribosomes, vesicles, prominent Golgi apparatus and lysosomes. 
    This process is mediated by osteoblasts, which release a number of chemical mediators. 
These, in turn, stimulate the synthesis of various factors that promote the proliferation of 
hemopoietic cells. 
    In the cortical bone, osteoblasts fuse to form a "cutting cone" that excavates a reabsorption 
tunnel to form a Harvesian canal. 
When the osteoclastic reabsorption is finished, bone formation ensues. Local release of chemical 
mediators, probably TGFb and IGF1, attract pre-osteoblasts that mature into osteoblasts and 
replace the missing bone by secreting new collagen and other matrix constituents.  
    Reabsorption and formation are complete within eight to twelve weeks, with several 
additional weeks being required to complete mineralization.  Under normal conditions, 
there is an equivalence in the action of osteoblasts and osteoclasts, 
so that the amount of bone reabsorbed is equal to the amount of bone replaced. 
    However, remodeling, like other biologic processes, is not entirely efficient, so that it 
may result into an imbalance. 
    The accumulation of bone deficits will be detected only after many years, suggesting that 
age-related bone loss may be a normal, predictable phenomenon beginning just after cessation 
of linear growth.  
    Given a normal, slightly negative balance, any stimuli that increases the rate of bone 
remodeling by having more sites involved in this process, will increase the rate of bone loss. 
    This is seen in thyrotoxicosis or primary hyperparathyroidism.  
    Other stimuli such as glucocorticoids excess, immobilization, ethanol abuse, smoking and age 
decrease osteoblastic synthetic activity and thus accelerate bone loss.  
    Bone density and fracture risk are determined not only by the rate of bone loss during adult 
life, but also by the maximum bone mineral acquired at skeletal maturity. 
    Pubertal growth is critical to forming an adequate peak bone mass because much of the 
total skeletal mass is deposited during this period of accelerated skeletal growth. 
    Other factors that contribute to peak bone mass are heredity and environmental factors such 
as muscular strength, physical activity and nutritional status. In addition, adequate levels of 
steroid hormones (testosterone and estrogen) are also necessary for the development of a satisfactory 
peak bone mass, so that hypogonadal adolescents show important deficits in cortical and trabecular 
bone mineral.  
    A woman who experienced interruption of menses, extended bed rest, an eating disorder or a 
systemic illness during her adolescence may enter adult life having failed to achieve the 
bone mass predicted by her genetic background, so that a normal rate of bone loss might lead to 
an osteoporotic state earlier, simply because of low starting bone mass.

Classification
    Primary osteoporosis is a condition of reduced bone mass and fractures found in 
menopausal women  or in older men and women.  
    Other causes of primary osteoporosis include idiopathic osteoporosis of childhood and 
hereditary conditions such as osteogenesis imperfecta and Marfan's syndrome.  
    Type I osteoporosis is six times more frequent in women than in men, and occurs between 
ages 50 and 65. It represents a loss of trabecular bone after menopause, related to loss of estrogen. 
    The loss of structural trabeculae weakens vertebrae and predisposes them to acute collapse; 
the vertebral fractures are usually of the "crush" type asociated with large deformation and pain.  
    The vertebral and Colles fractures are common, because vertebral body and distal radius contain 
large amounts of trabecular bone.  
    On the other hand, type II osteoporosis is only two times more frequent in women than 
in men, and occurs in more advanced ages (75 years or more). It is an age-related process. 
    The loss of bone mass is slower and affects both cortical and trabecular bones. It is related to 
a decrease in serum 1,25 (OH)2 D3 due to a reduced renal function. 
    Low levels of active vitamin D will decrease intestinal absorption of calcium, causing 
secondary hyperparathyroidism and consequently bone atrophy.  
    The fractures occur most often in vertebrae and femoral neck, followed by pelvis, humerus and tibia.   
    Secondary osteoporosis refers to bone loss resulting from specific clinical disorders, 
and may include a large number of causes: 
a) endocrine diseases: hypogonadism, thyrotoxicosis, hyperparathyroidism, Cushing's 
syndrome, amenorrhea and others; 
b) functional conditions: physical inactivity, prolonged immobilization; 
c) gastrointestinal disturbances: hepatic insufficiency, post-gastrectomy, chronic pancreatitis, 
chronic inflammatory diseases, reduced calcium absorption; 
d) chronic inflammatory conditions: rheumatoid arthritis, serum-negative spondyloarthropaties, 
systemic sclerosis; 
e) hematologic diseases: myeloma, mastocitosis; 
f) drugs: heparin, glucocorticoids, lithium, methotrexate, retinoids, anticonvulsant, anti-acids, 
interleukines.  
    Risk Factors 
a) low risk: afro-caribbeans, strength and muscular resistance, multiparity, high calcium 
intake, moderate physical activity, obesity, fluor ingestion (added to water), drugs 
(estrogen, thiazides, diuretics and calcium supplementation); 
b) high risk: caucasians and asiatics, smoking, alcoholism, long period of immobilization 
and inactivity, physical inactivity, primary amenorrhea, secondary amenorrhea, precocious menopause 
(idiopathic, oophorectomy), nuliparity, nutritional factors (low calcium intake, high caffeine 
consumption, sodium intake), drugs ( gluco-corticoids, anticonvulsant, heparin, thyroxine), 
family history, low stature and small bones.
    The dairy industry has used osteoporosis as a marketing tool, but milk is not  the answer. 
    In countries where dairy products are commonly consumed, there are actually more hip fractures 
than in other ones. 
    When put to the test, most studies show that dairy products have little effect on osteoporosis. 
    As surprising as that may be, when researchers have measured bone loss in postmenopausal women, 
most have found that calcium intake has little effect on the bone density of the spine. 
    There is also little or no effect on bone at the hip, where serious breaks can occur. 
    Some studies have found a small effect from calcium intake on bone density in the forearm.   
    The overall message seems to be that, as long as you are not grossly deficient in calcium, 
supplements and dairy products do not have much effect.  Why not? For one thing, the amount of calcium 
in the bones is very carefully regulated by hormones. Increasing your calcium intake does not 
fool these hormones into building more bone, any more than delivering an extra load of bricks 
will make a construction crew build a larger building.  
    If milk, or calcium intake in general is not a good hedge against bone loss after menopause, 
how about before menopause? That too seems to follow the pattern.  Milk does contain calcium. 
But milk neither assures strong bones in childhood nor does it protect bones in adulthood. 
    For the vast majority of people, the answer is not boosting calcium intake but, rather, 
limiting calcium loss. 
    As surprising as it sounds, one major culprit in osteoporosis may be protein. Diets that are 
high in protein, especially animal protein, cause more calcium to be excreted.  
    When volunteers eat high-protein meals, they lose calcium in their urine. If they consume 
more modest amounts of protein, they lose much less calcium in their urine. What is apparently 
happening is this: amino acids cause the blood to become slightly more acidic. To neutralise 
this acidic effect, bone material is dissolved, which is believed to lead to the loss of calcium 
in the urine.  
    The problem is not just the quantity of protein consumed but also the type of it. 
    Meats are high in a type of protein building block called sulfur-containing amino acids. 
    These are particularly likely to aggravate calcium loss. Meats also contain large quantities 
of phosphorus, which can impair calcium balance.  
    Although the role of phosphorous in osteoporosis is far from clear, scientists believe that 
diets in which phosphorus and calcium intake are roughly equal help keep calcium in the body, 
while diets in which the two are unbalanced are thought to harm calcium balance. 
    Beef has a high phosphorus-to-calcium ratio, about 15:1. Chicken breast is similar, about 14:1, 
a peach is about 2:1. Boiled broccoli has a phosphorus-to-calcium ratio of about 0.4:1.  
    Green leafy vegetables provide generous amounts of calcium without the animal protein of meaty diets. 
    In fact, green vegetables such as broccoli, kale, etc. are loaded with calcium and calcium 
absorbability is actually higher for kale than for milk. 
    One cup of milk contains 291mg of calcium.  But only about 30 percent of it is absorbed, 
and that glass of milk also contains 8 grams of animal protein to encourage the loss of calcium. 
    Green vegetables, beans, and enriched flour are rich in calcium, and fortified orange juice 
supplies substantial amounts of calcium.  
    Fruits and vegetables also provide boron, an element which appears to be important in 
preventing the loss of calcium. The best way to get boron, is through a balanced diet containing 
an abundance of fruits, vegetables, nuts and legumes; wines also. Animal products, including milk, 
have little or no boron.  
    Hormones play a major role in bone structure. After menopause, bone loss is often aggressive, and 
the prescription of hormone replacements is effective in delaying osteoporosis. 
    Exercise is also important.  If bones are not being used, they have little reason to preserve 
their strength. 
    In addition, alcohol and tobacco aggravate bone loss. 
    When replacement hormones are used, calcium supplements have been shown to be a helpful 
adjunct in slowing bone loss.

Diagnosis
a) radiologic studies: signs of osteoporosis such as bone rarefaction and vertebral compression 
are only present when we have a reduction of 30% or more in bone mass, and thus are not useful 
if the aim is an early diagnosis; 
b) the dual photon absorptiometry (DPA), which uses 153Gadolineum. It can correct the 
contribution of soft tissues.  
    The method used nowadays is the dual energy X-ray absorptiometry (DEXA), in which the 153Gadolineum was 
substituted by the X-ray. 
    The advantages include a greater reproducibility, a lower dose of radiation, and better resolution. 
The limitation is that it cannot differ osteoporosis from osteomalacia.  
    It is recommended a one year interval in serial densitometries in the monitoring of 
osteoporotic individuals. 
    Bone Turnover Markers
    These substances represent either a metabolite of bone matrix breakdown, such as pyridinoline 
or have an enzymatic activity related to bone formation, such as alkaline phosphatase.  
    Markers of bone formation include osteocalcin, alkaline phosphatase and type I procollagen 
extension peptide. 
    All of them are secretory products of osteoblasts during bone matrix synthesis.  
    Alkaline phosphatase is the most used marker to estimate bone formation, but it is not 
specific for the bone as it includes other sites of production, such as the liver and small intestine.  
    Markers of bone reabsorption include urinary hydroxiproline and piridinoline, both of which 
reflect collagen breakdown. 
    Hydroxiproline is an aminoacid essentially unique to collagen and is not catabolized in the body.  
    Piridinoline and desoxipiridinoline are specific for bone turnover and are not metabolized 
in vivo, thus having more specificity and sensitivity than hydroxiproline.  
    Bone biopsy studies provide definitive diagnosis of mastocitosis and myeloma and 
remains the gold standard for excluding osteomalacia. 
    It is an invasive study and should be reserved for patients with unusual, unexplained disorders; 
for patients in whom myeloma or mastocitosis requires exclusion; for those in whom osteomalacia 
is suspected and for patients with post-menopausal osteoporosis who are in serious condition 
and whose bone turnover markers are inconclusive.

Differential Diagnosis
    It is necessary to differ primary from secondary osteoporosis; post-menopausal and senile 
osteoporosis. 
    The great majority of factors that cause osteoporosis can be identified by the clinical history 
and the physical exam. 
    The screening tests that should be performed in any case of osteoporosis include: 
serum calcium, serum phosphorous, evaluation of renal function, blood count test plus ESR 
(important in the evaluation of myeloma) and urinary calcium. The last one is important to 
identify a subset of patients who are rapidly reabsorbing bone and who need additional attention 
to identify the cause.  
    More specific evaluation can be performed as in cases of detection of hypercalcemia where 
measurement of serum intact PTH should be required. 
    When Cushing's syndrome is suspected, an overnight dexamethasone-suppression testing should be performed.

Treatment
    Calcitonin reduces acute pain associated with osteoporotic fractures and has 
been found useful in treating chronic back pain following vertebral fractures in spinal osteoporosis.  
    Side effects are dose related and generally mild; they include gastrointestinal, vascular 
and dermatologic conditions that can be treated symptomatically or by varying the dosage. 
    Side effects are much rarer with nasal administration than with injection. 
    True allergic reactions are rare. 
    Calcitonin may also prevent postmenopausal bone loss and increase bone density in those with 
established osteoporosis.  
    Osteoporotic vertebral fractures may be asymptomatic and detected only on radiologic investigation. 
    In many cases, however, vertebral fractures can produce significant pain and debility, 
which can persist for many months following the fracture. Calcitonin has been used to 
treat pain associated with a number of bone conditions, including Paget's disease and metastatic 
bone disease, as well as for the pain from vertebral fractures that occur as a result of osteoporosis. 
    In each condition, pain relief begins within the first several days following initiation of therapy.  
    The effects of pain reduction persist for at least the first  month of administration. 
    Chronic back pain can develop following vertebral fractures in spinal osteoporosis. 
The mechanisms may include persistent injury to the vertebrae, degenerative changes subsequent 
to the fracture and pain originating from paraspinal tissues resulting from abnormal anatomical 
positioning and spinal malalignment. 
    Calcitonin may provide pain relief if it's instituted anytime within the first year after fracture, 
although data suggest that the benefit is greater the earlier the drug is administered.  
    Data are limited on the use of calcitonin for relief of pain following fracture at 
nonvertebral sites or in secondary osteoporosis.  
    Several studies, mostly of short duration (1 to 2 years), have demonstrated the efficacy of 
calcitonin in preventing bone loss in the early postmenopausal period.  
    Antibodies to calcitonin, particularly to fish calcitonin, develop in a significant 
proportion of patients receiving long-term treatment. 
    There is some concern that these antibodies may diminish the efficacy of calcitonin, but 
the extent to which they interfere remains unresolved.  
    Data on hip fractures from prospective, controlled studies are limited. 
    There are no control data on fracture risk in men, in premenopausal women or in secondary osteoporosis. 
    There is no information on whether apparent benefits are sustained beyond 2 years of 
calcitonin treatment.  
    Calcitonin may be indicated for the female with osteoporosis in whom estrogen is contraindicated. 
    The recommended dose is 100 units SQ qd but few patients will tolerate this dose initially; 
consider starting with 25 units 3 times a week.  
    Estrogen is commonly given to postmenopausal women for osteoporosis prevention and to 
reduce the risk of heart disease.  
    Approximately 50% of postmenopausal women need some sort of therapy to maintain their bones 
above the fracture threshold until the age of 70. 
    Moreover, nearly all women need therapy if they wish to keep their bones above the fracture 
threshold for an entire life to age 80 or 90. 
    Taking postmenopausal estrogen replacement is easy, avoids hot flashes, and effectively 
retards the loss of bone minerals. 
    A lot of research has been going on to develop drugs that provide the beneficial effects 
of estrogen while avoiding the detrimental ones. 
    In 1995 the first of a series of new drugs, bisphosphonates, was approved for treating 
postmenopausal osteoporosis. 
    The first of these drugs was alendronate, and in 1997 risedronate was approved.  
    Risedronate is less irritating to the stomach than is alendronate. 
    Women with low bone mineral density or a prior history of fracture after age 40 are among 
those most likely to benefit from treatment with alendronate sodium 10 mg daily; 
it increases the bone density at the lumbar spine, proximal femur, and total body. 
    Moreover, the incidence and severity of new vertebral fractures is significantly reduced 
by the alendronate treatment. 
    As with all bisphosphonates, alendronate must be taken on an empty stomach - at least one hour 
before any food or medication - to ensure absorption. Bisphosphonates should not be used at all 
in persons with impaired kidney function and in patients with hypocalcemia. 
    In 1997 the first of another type of  hormone-like drug, raloxifene, was approved for 
osteoporosis prevention. 
    In contrast to estrogen, these drugs have no untoward breast effects and actually increase bone 
mineral density. 
    An estrogen derived from plants was shown in clinical trials to prevent osteoporosis at half 
the dose of the animal-based estrogen and with fewer side effects.  This low dose, plant-based 
estrogen doesn't cause the increase in vaginal bleeding or endometrial hyperplasia, a precursor to 
endometrial cancer.   
    The majority of women who start estrogen-replacement therapy quit within one or two years 
due to side effects, thereby preventing the long-term protective effects of estrogen on bone 
and cardiovascular health.  
    The study also suggests that the hormone progestin, a complementary component of estrogen 
replacement therapy in women with an intact uterus, may not be needed, or may be required at a 
lower dose. Reducing levels of progestin could be beneficial, as progestin often causes undesirable 
side effects, including bleeding, breast tenderness and pain, bloating, cramps and depression.  
    The same idea could apply to the use of soybeans because of its estrogen-like effects.  
    Long-term administration of low doses of corticosteroids is common in the treatment of autoimmune 
diseases, chronic obstructive lung disease, asthma, and allergic conditions. 
    Although treatment with high doses of corticosteroids causes osteoporosis (especially in 
trabecular bone, such as that found in the lumbar spine, use of corticosteroids in low doses 
was thought to be associated with few substantial side effects. However, these low doses of 
corticosteroids is also associated with loss of bone mineral density in the lumbar spine and 
that patients receiving continuous therapy with low-dose corticosteroids have a higher rate 
of vertebral fracture. 
    Corticosteroids cause osteoporosis by several mechanisms, such as decreasing levels of sex 
steroids and direct effects on osteoblast and osteoclast function . Use of corticosteroids also 
decreases absorption of intestinal calcium  thereby causing secondary hyperparathyroidism. 
    Some studies have shown that vitamin D3 and its more potent analogues can improve calcium 
absorption in patients receiving corticosteroids. 
    Vitamin D3, is generally well tolerated and rarely causes side effects when used in 
the recommended dosage (400 to 800 IU/d). 
    Vitamin D3 and calcium carbonate 1000 mg per day should be given to all patients receiving 
long-term corticosteroid therapy.  
    Also calcium and 1,25 vitamin D is the primarily treatment for type II (senile) osteoporosis.  
    In our experience we've seen that practically in all patients 7-10 days after starting calcium 
and vitamin D3 the pain falls drastically, needing no more any other type of analgesic.  
    The primary function of vitamin D is to maintain skeletal calcium homeostasis.  Proper functioning 
of the vitamin D system is necessary for PTH to maintain plasma calcium effectively, although 
drops in the plasma calcium occur only with severe vitamin D depletion; it appears that 
only minute amounts of vitamin D are necessary for PTH to carry out its actions on the bone and kidney.  
    Biosynthesis: provitamin D2 (ergocalciferol from certain plants and animal fat) and 
7-dehydroxycholesterol (endogenous) to form cholecalciferol (vitamin D3); provitamin D3 
(7-dehydroxycholesterol synthesized in liver and stored in skin); in the skin, the provitamin is 
converted to the active form of cholecalciferol through the activity of ultraviolet irradiation; 
hepatic hydroxylation to 25-OH vitamin D3; renal hydroxylation to 1,25 di OH D3. 
    Remember that high doses of vitamin D may be toxic, and toxicity has occurred at levels as 
low as 2.000 to 5.000 UI/day.  
    NaF therapy stimulates bone formation and may be effective in preventing osteoporotic fractures. 
    Initial evidence that fluoride ingestion results in increased density of spinal bone was obtained 
in 1937 from roentograms of patients who had been exposed to toxic levels of fluoride in an 
industrial setting. 
    Fluoride acts by stimulating osteoblastic bone formation, and it is the most potent stimulator 
of bone formation known. The effect is almost exclusively on the weight-bearing skeleton, primarily 
the spine. 
    The reason for this site selectivity is not known. 
    The increase in spinal bone mass generally amounts to 5% to 10% annually. The precise cellular 
mechanism of action is not known, but fluoride appears to act primarily on primitive 
osteogenic cells by sensitizing the skeleton to the effects of various skeletal growth 
factors through phosphotyrosyl phosphatase inhibition, tyrosine kinase stimulation or both. 
    Aluminum may be a necessary cofactor, and recent in vivo evidence links the uptake 
of these two ions to bone.  Toxic effects are dependent on formulation and dosage.  
    Gastrointestinal toxicity is negligible and, because the drug is not absorbed in the stomach, 
it can be given together with a calcium supplement.  
    Widespread clinical experience with the use of fluoride over the past 30 years has not led to 
any suspicion about increased risk of human cancer.  
    Potential areas of use are in patients who cannot or will not take estrogen, in patients who are 
refractory to treatment with estrogen or bisphosphonates, in patients with premenopausal osteoporosis 
and corticosteroid-induced osteoporosis and in some patients with mild osteogenesis imperfecta.