Today, we recognize that osteoporosis occurs across all age groups and affects both genders. Osteoporosis is recognized as a disorder of bone remodeling that leads to deformations in the bone micro/macroarchitecture, and a decrease in, or loss of, bone mass and density. With these events bone loses strength, becomes fragile, and as a consequence, is prone to fracture.
Bone turnover or remodeling is a finely orchestrated process involving interactions between osteoblasts, osteoclasts, and osteocytes. By some estimates, the skeleton is completely remodeled every 10 years. For a healthy individual, more bone is formed during the first three decades of life than is lost, with peak bone mass and density occurring between ages 30 and 36. After this, more bone is lost on an annual basis than formed, although the rate of loss is hardly noticeable for most (< 1% each year in both genders). When a woman enters menopause, the rate of loss accelerates and as much as 2% is lost each year for about 5 years or so.
Accelerated bone turnover is problematic because the bone formed is often of poor quality. Cortical bone becomes more porous. Trabeculae become thin, and gaps are often found between neighboring trabeculae where connections should be. As a result, bones become weak and less able to endure "normal" stresses. For many women, some, as yet undetermined, process causes the rate of turnover to slow down after about 5 years and bone continues to be lost but at a slower rate. For others, as in the case of our patient, bone turnover continues at an accelerated rate and leads to osteoporosis.
Generally, estrogen deficiency is thought to be the dominant factor leading to osteoporosis regardless of gender. It is clear, however, that other hormones and local factors contribute to bone health and disease, including androgens, calcitonin, parathyroid hormone, thyroxin, vitamin D, vitamin K, ionized calcium, insulinlike growth factors (IGFs), transforming growth factors (TGFs), platelet-derived growth factors (PDGFs), and interleukins (ILs).
Type 1 osteoporosis is characterized by an accelerated rate of bone resorption—in other words, high bone turnover—in response to declining estrogen concentrations. Calcium concentrations increase, leading to suppression of parathyroid hormone (PTH) secretion. This form of the disease occurs at a greater frequency in women and typically has the greatest impact on trabecular bone. As mentioned previously, all women undergo an accelerated loss of bone mass with menopause. In type 1, the rate of loss does not diminish after a few years but continues at an accelerated rate for another 10-20 years if left untreated.
In type 2 osteoporosis bone loss occurs slowly, beginning as early as age 40, continues over several decades, and may not be recognized before the individual has reached age 70. The disturbance in bone remodeling appears to be more osteoblast-related; osteoclasts create a resportion cavity of normal or even less-than-normal depth, but impaired osteo-blast activity leads to less matrix formation. As a result, both trabecular and cortical bone are affected.
Although some suggest that the type of osteoporosis isn't important since the treatment is the same, the facts remain that there are differences between types 1 and 2 in the onset, severity, and which type of bone is most involved. These make a difference in terms of the fractures encountered. In type 1, fractures of the vertebrae, wrist, and ankle are more common. The vertebral fractures are usually the crush types that cause deformation and pain. As these occur, patients lose up to 25% of their vertebral height. Another indicator may be new onset of tooth loss despite good oral hygiene because the jaw, mandible, and maxilla contain significant amounts of trabecular bone. In type 2, fractures occur most commonly at the hip, proximal humerus, proximal tibia, and pelvis. The vertebral fractures that these patients experience occur typically in the mid-thoracic area, cause less pain, occur gradually, and lead to the formation of a deformation known as dorsal kyphosis, or "dowager's hump."
The relationship between osteoporosis and estrogen deficiency in women was first suggested by Albright in 1941. More recently, decreased estrogen and testosterone have been implicated in the development of the disease in men. Estrogens exert a beneficial effect on bone through two primary mechanisms: (1) they hold bone resorption in check by inhibiting synthesis of specific cytokines (particularly IL-1 and IL-6) that are known to stimulate bone resorption; and (2) they enhance local synthesis of growth factors such as TGF-b and TGF-1 that stimulate PTH-mediated bone formation.
Abnormalities in bone turnover also occur secondarily to a number of other diseases and medications (see Table 30.1). Since the resulting bone loss can be slowed or stopped if the primary disorder is treated, it is important that the workup of these patients also include evaluation of the more common disorders and a review of medications.
The thyroid hormones, T3 and T4, contribute to normal bone development and metabolism. Increasing concentrations of these hormones stimulate osteoclast activity and consequently bone resorption by activating receptors on osteoblasts. Although formation is also stimulated, the rate of resorption is greater. Parathyroid hormone (PTH) also plays key roles in both formation and resorption. Osteoblasts, but not osteoclasts, have receptors for the hormone, so both actions appear to be mediated through the osteoblasts. Continuous, high-dose exposure to PTH (as occurs in primary hyperpara-thyroidism) inhibits bone collagen synthesis and increases bone resorption, whereas collagen synthesis and bone formation are stimulated with intermittent, low-dose exposure
Table 30.1 Causes of Secondary Osteoporosis
Osteogenesis imperfecta, glycogen storage diseases, homocystinuria,
Marfan syndrome, amyloidosis, rheumatoid arthritis Malignancies, microgravity, prolonged bed rest, chronic liver diseases, chronic obstructive pulmonary disease, amyloidosis, malabsorption Glucocorticoids, thyroxine, heparin, cyclosporine, tacrolimus, aromatase inhibitors, LH-RH agonists, diuretics, ethanol, neuroleptics, aluminum, antacids (phosphate binders), methotrexate, anticonvulsant drugs, lithium, cholestyramine
Medications of bone to PTH. These two paradoxical events relate to production and stimulation of local factors like macrophage-colony-stimulating factor (m-CSF), nuclear factor-kb ligand (RANKL), and osteoprotegerin.
Excess glucocorticoids regardless of the cause (tumor, hyperplasia, or ingestion), has a negative impact on bone. Through their effects on growth factors, carrier proteins, and cytokines, the hormones stimulate proliferation of osteoclasts while inhibiting maturation of osteoblasts. Glucocorticoids also directly inhibit intestinal transport and renal reabsorption of calcium leading to secondary hyperparathyroidism, as well as stimulating the parathyroids to increase PTH secretion.
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