Photo 1. The normal trabecular bone(microphotography)
Photo2. The osteoporotic trabecular bone(microphotography)
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. See photo 1 and 2
It is a frequent osteometabolic disease, with a high morbidity, frequently associated with hip and vertebral fractures.
Actually, osteoporosis is a syndrome, since there are a lot of conditions that can lead to this state of bone fragility. It is a national health problem due to its high prevalence and incapacitating complications, such as pain and fractures. Its prevention can avoid the large expenditure caused by the treatment of the resulting pathological 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 very important role in its pathogenesis.
It is estimated that 50% of osteoporosis femur fractures expand to total or partial incapacity and that 20% to 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 in osteoporosis are vertebral, distal radius (Colle’s fracture) and ribs. However, femur fractures are the major cause of morbidity, eventually leading to death.
Appreciation of the mechanisms through which osteoporosis develops requires an understanding of bone remodeling , that is, a continuous cycle of destruction and renewal carried out by specific cells. 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, were they fuse into multinucleated osteoclasts. 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.
So, we can see that bone turnover is a process regulated by a macro system (circulating hormones) integrated into a local micro system (local growth factors, citokines, etc...).
Reabsorption and formation are complete within eight to twelve weeks, with several additional weeks being required to complete mineralization.
It is known that 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, in 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.
It is important to mention that 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 (perhaps 60%) 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. As we can see, physical activity and an intake of calcium in the adolescence are very important in determining the peak bone mass and thus can prevent osteoporosis in adulthood. 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.
Osteoporosis can be classified in primary and secondary.
Primary osteoporosis is a condition of reduced bone mass and fractures found in menopausal women (post-menopausal osteoporosis ¾ type I) or in older men and women (senile osteoporosis ¾ type II). 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. 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.
Secondary osteoporosis refers to bone loss resulting from specific clinical disorders, and may include a large number of causes:
- Endocrine diseases - hypogonadism, thyrotoxicosis, hyperparathyroidism, Cushing’s syndrome, amenorrhea and others.
- Functional conditions - physical inactivity, prolonged immobilization.
- Gastrointestinal disturbances - hepatic insufficiency, post-gastrectomy, chronic pancreatitis, chronic inflammatory diseases, reduced calcium absorption.
- Chronic inflammatory conditions - rheumatoid arthritis, serum-negative spondyloarthropaties, systemic sclerosis.
- Hematologic diseases - myeloma, mastocitosis.
- Drugs - heparin, glucocorticoids, lithium, methotrexate, retinoids, anticonvulsant, anti-acids, interleukines.
Low risk related factors in osteoporosis: 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).
High risk related factors in osteoporosis: caucasians and asiatics, smoking, alcoholism, long period of immobilization and inactivity, physical inactivity, primary amenorrhea, secondary amenorrhea, precocious menopause (idiopathic, oophorectomy, hysterectomy), nuliparity, nutritional factors (low calcium intake, high caffeine consumption, low protein, fiber and sodium intake), drugs ( glucocorticoids, anticonvulsant, heparin, thyroxine), family history, low stature and small bones.
Radiologic Studies:
Radiologic 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.
There are now several non invasive methods available to access bone mass with reasonable accuracy and precision. The first one to be used for this purpose was the single photon absorptiometry (SPA). This method is only used in skeletal appendages, because it cannot correct the attenuation caused by soft tissues. As the bone mass on these sites does not correspond to the bone mass in critical areas of fractures, such as the vertebral bones, its applicability is limited.
Several studies made possible the development of another method, called dual photon absorptiometry (DPA), which uses 153Gadolineum. This method can correct the contribution of soft tissues and thus made possible the measurement of bone mass in areas of more clinical interest.
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. It is also a non-invasive and low-cost method. The limitation is that it cannot differ osteoporosis from osteomalacia.
Osteopenia is defined as a bone density between 1- 2.5 SD (Standard Deviation) below the mean density of the bone mass peak. Osteoporosis is defined as a bone density below 2.5 SD. Bone density between 0 - 1 SD is considered normal.
It is recommended a one year interval in serial densitometries in the monitoring of osteoporotic individuals.
Quantitative computed tomography (QTC) is another method that can be used for the evaluation of bone density, and it separates trabecular trabecular from cortical bone. The high doses of radiation, the high cost and the difficulties to access this method limit its use as a routine test. Ultrasound is another method that has been considered, and it has the advantage of low-cost.
Bone Turnover Markers:
Aside from other osteometabolic diseases, such as renal osteodistrophy, osteoporosis is characterized by only slight increases in bone turnover; so, the evaluation of osteoporosis requires highly sensitive markers.
In general, 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. It is thought that these markers, along with densitometric studies, would help the identification of women with rapid loss of bone mass, allowing an earlier diagnosis.
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. Of these, the first two are available for clinical use and show correlation with bone formation rate.
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. In the absence of other conditions that interfere with alkaline phosphatase activity, this marker will indirectly represent bone formation. Nowadays, it is available the measurement of specific alkaline phosphatase derived from osteoblasts.
Several studies showed that osteocalcin is a more sensitive marker than total alkaline phosphatase in determining bone formation.
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. It is derived from various types of collagen and thus it is not specific of bone tissue. It is neither a sensitive method as it is metabolized in the liver.
Piridinoline and desoxipiridinoline are specific for bone turnover and are not metabolized in vivo, thus having more specificity and sensitivity than hydroxiproline.
The simultaneous study of bone reabsorption and formation by these multiple markers has more applicability than the study an unique marker.
Bone Biopsy Studies:
These 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 patients in whom osteomalacia is suspected and for patients with post-menopausal osteoporosis who are in serious condition and whose bone turnover markers are inconclusive.
As we could see by the previous exposition, osteoporosis can be due to several causes. First of all, it is necessary to differ primary from secondary osteoporosis. Post-menopausal and senile osteoporosis should be considered an exclusion diagnosis, as this pathologies do not have any specific marker. The great majority of factors that cause osteoporosis can be identified by the clinical history and the physical exam. But, sometimes, they will only be determined after some screening tests, that can be followed by more specific ones related to the suspected disease.
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.
1. Cecil; Textbook of Medicine 20th edition; 1379-83
2. Harrison; Medicina Interna; 13a edição; 2282-7
3. MKSAP in the subspecialty of Endocrinology and Metabolism; 153-60
4. São Paulo Medical Journal; Osteoporosis 1995 - Basic diagnosis and therapeutic elements for a “National Consensus Proposal”
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