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Chapter 28 Osteoporosis
Presentation: 2005
谢瑞满 Rui-man Xie ， Ph.D., M.D.
Professor of Neurology & Gerontology
ZhongShan Hospital, Fudan University
Objective
1 、 Definition 、 types and mechanism of osteoporosis
2 、 Diagnosis 、 prevention and treatment of osteoporosis
3 、 Etiology and Epidemiology of osteoporosis
times – 45 minutes×2
Overview
Definition : Osteoporosis is a bone disease in which the amount of bone is decreased and the structural integrity of trabecular bone is impaired. Cortical bone becomes more porous and thinner. This makes the bone weaker and more likely to fracture.
figures
Associated changes in body shape and vertebra （ deleted 6 pictures）
normal
50yrs above 55yrs
above 75yrs
kyphosis
Patients with risk factors or conditions that cause osteoporosis
Postmenopausal woman with family history of hip fractures or kyphosis
Medications: corticosteroids, dilantin, gonadotropin releasing hormone agonists, loop diuretics, methotrexate, thyroid, heparin, cyclosporin, depot-medroxyprogesterone acetate
Hereditary skeletal diseases: osteogenesis imperfecta, rickets, hypophosphatasia
Endocrine and metabolic: hypogonadism, hyperparathyroidism, hyperthyroidism, Cushing syndrome, acidosis, Gaucher's disease
Marrow diseases: myeloma, mastocytosis, thalassemia Others: Anorexia, Malabsorption, Cystic fibrosis, Renal
insufficiency, Hypercalciuria, Hepatic disease, Depression, Spinal cord injury, Systemic Lupus, Weight below healthy range, Cigarette smoking
Epidemiology The population of older men and women has
been increasing, and therefore the number of people with osteoporosis is increasing.
In the USA, about 21% of postmenopausal women have osteoporosis (low bone density), and about 16% have had a fracture. In women older than 80, about 40% have experienced a fracture of the hip, vertebra, arm, or pelvis.
Women have more osteoporotic fractures than men. Age is one of the most important risks in all groups.
The decreased physical activity may be playing a role in increased hip fractures.
Mechanism : Bone physiology The bone is continuously remodelling, and the bone surface
moves in and out. The Basic Multicellular Unit (BMU) is a wandering team of cells that dissolves an area of the bone surface and then fills it with new bone. The sequence is Origination, Osteoclast recruitment, Resorption, Osteoblast recruitment, Osteoid formation, Mineralization, Mineral maturation, Quiescence.
Bone strength (Quality): In addition to bone porosity, the bone strength is determined by the trabecular microstructure. Perforations of individual trabecula occur when resorption cavities are too deep. This, too, is seen with estrogen deficiency. The remaining trabecula are not as well connected and are mechanically weaker.
Mechanism : Bone physiology Microfracture healing is another aspect of bone strength
that is not measured by bone density. Trabeculae inside the bone may fracture and microcalluses are formed that resemble the calluses seen on xrays of long bones after a "macro-fracture". Osteoporotic bone is more susceptible to these fractures because the individual trabeculae do not have as many reinforcing connections. The calluses may represent a method of repairing the bone and even connecting some of the trabecula. Bone which has lost the ability to form these calluses will be weaker.
The age of the bone mineral crystals may also play a role in the strength of bone. This is an area that needs further research. Studies suggest that older bone is more brittle, and that one purpose of bone remodelling is to remove the old bone and replace it with newer, more elastic bone.
Clinical manifestation and types Secondary osteoporosis： Mndocrine and metabolic: hypogonadism,
hyperparathyroidism, hyperthyroidism, Cushing syndrome, acidosis, Gaucher's disease;
Marrow diseases: myeloma, mastocytosis, thalassemia; Medications: corticosteroids, dilantin, gonadotropin
releasing hormone agonists, loop diuretics, methotrexate, thyroid, heparin, cyclosporin, depot-medroxyprogesterone acetate;
Malabsorption 、 Hepatic disease, others； Hereditary skeletal diseases: osteogenesis imperfecta, rickets, hypophosphatasia; Primary osteoporosis.
Clinical manifestation and types
Primary osteoporosis ：Type postmenopausal osteoroposisⅠ ——This is
seen with estrogen deficiency. There is high bone turnover rate. The proportion of trochanteric and femoral neck fractures increases ；
TypeⅡ elderly osteoroposis——This is aging in bone physiology. The compression fracture of the spine and hip fracture are more common.
Clinical Features of Osteoroposis
The vast majority of hip fractures occur after a fall. About 5% appear to be “spontaneous” fractures, in which the patient feels a fracture and then falls.
Overall about half of hip fractures are intertrochanteric and the others are femoral neck fractures.
Clinical Features of Osteoroposis Vertebral compression fractures vary in
degree from mild wedges to complete compression. The symptoms also vary, but the degree of compression is not necessarily related to the amount of pain. In fact, about 60% of women with compression fractures do not realize they have had a fracture! It is possible that some of the fractures occurred gradually and therefore did not cause acute pain.
Clinical Features of OsteoroposisWhen women and men do suffer painful
compression fractures, the pain usually lasts from one to two months, is localized to the back with accompanying muscle spasms, then gradually subsides.
Patients with continuing severe pain should be evaluated for other pathologic etiologies of the fracture, especially malignancy or myeloma.
Persistent pain can also be caused by continuing fracture, muscle spasms, spinal stenosis, or degenerative joint disease.
Clinical Features of OsteoroposisTo correctly interpret a spine xray, it is
important to know the definition of a vertebral fracture, which is not quite as straightforward as it first appears, especially for research.
For practical clinical purposes, a vertebra can be considered fractured if the anterior height is 80% or less of the posterior height.
A new fracture requires loss of at least 20% of anterior or posterior height.
Clinical Features of Osteoroposis Wrist fractures are more common in women who
are 50 to 60 years old. These are caused by falls or other trauma. Osteoporosis does not appear to impair the healing of the wrist fractures, and they cause only short-term disability.
Although spine, hip, and wrist fractures are considered classical osteoporotic fractures, many others are related to bone density and thus are also osteoporotic. These include rib, pelvic and shoulder fractures, but not finger, facial bone, skull, elbow, or ankle fractures.
Clinical Features of Osteoroposis
The irreversible height loss associated with osteoporosis is one of the aspects of the disease that is most distressing to many women.
Height loss can also occur with scoliosis, which often gets worse after menopause.
Also, degenerative disk disease can cause height loss of 2 inches.
Some reversible height loss is due to poor posture.
KYPHOSIS is the feature of osteoporosis that is identified by most patients. The hump causes difficulty in finding clothes that will fit, let alone look attractive. In severe cases, the ribs contact the iliac crest and movement causes pain.
Clinical Features of OsteoroposisPROTRUDING ABDOMEN The protruding abdomen which is a result of
the kyphosis is an unrecognized aspect of osteoporosis. Women do not realize that the curvature of the spine decreases the abdominal space, and thus the intestines have nowhere to go except forwards. Many women think that they are getting fat, and they go on a diet trying to regain their youthful waistline. If they do successfully lose weight, it will only increase their risk for more osteoporotic fractures.
Clinical Features of Osteoroposis
DECREASED PULMONARY CAPACITY
Patients with kyphosis have decreased
lung volumes. In severe cases this
leads to shortness of breath and
pulmonary symptoms of restrictive lung
disease.
Clinical Features of OsteoroposisREFLUX ESOPHAGITIS
Patients with kyphosis may develop
reflux esophagitis due to the changes
in abdominal space. Wearing tight
clothing can exacerbate the problem.
Laboratory tests For an uncomplicated patient with
osteoporosis, a lab workup would be a chemistry panel, CBC, phosphate, TSH and 24-hour urine calcium. Males should have testosterone measured.
The main purpose of laboratory tests is to check for secondary causes of osteoporosis such as cases of renal or hepatic failure, anemia, acidosis, hypercalciuria, and abnormalities of calcium/phosphate.
Laboratory tests Alkaline phosphatase is an inexpensive
method of checking for osteoblastic activity. It is not as sensitive or specific as newer "bone markers" but it will detect moderate to severe osteomalacia or Paget's disease.
The 24-hour urine calcium measurement is frequently ignored but it is a valuable and inexpensive test. High levels are seen in idiopathic hypercalciuria, and low levels suggest malabsorption.
Laboratory tests Protein electrophoresis should be done
whenever a patient presents with new fractures. Both serum and urine tests should be done because some patients with myeloma have abnormalities in only one.
Corticosteroid excess that causes osteoporosis can usually be detected clinically by Cushingoid features. A urine cortisol can be helpful in puzzling cases.
Laboratory tests Gonadal hormones are very important causes
of osteoporosis. In females who are postmenopausal, it is not helpful to measure levels of estrogens or gonadotropins. In males, however, testosterone levels should be measured because there is much greater variability in the prevalence of hypogonadism. Also, men may have low testosterone without other clinical symptoms.
Laboratory tests Vitamin D and parathyroid hormone levels are expensive
tests. Mild vitamin D deficiency frequently occurs in the absence of hypocalcemia, but if vitamin D supplementation is routinely given, it is not necessary to perform this test in patients with normal calcium. Primary hyperparathyroidism nearly always causes hypercalcemia. Secondary hyperparathyroidism may occur with normal calcium, but most of these cases will be detected by low urine calcium or decreased renal function.
In patients with abnormal serum calcium or with unusually severe bone disease, however, the 25-OH-vitamin D and parathyroid hormone levels should be measured.
The 25 OH-vitamin D is more useful than the 1,25 (OH)2 vitamin D level.
Indications for bone density measurements
Over the last decade there have been many debates about screening bone density. Several organizations have performed detailed cost-benefit studies and developed guidelines; these must be continually revised as new findings about treatment effects are discovered.
Bone density tests carry no physical risks, but there is a problem of over-interpretation of results, so that healthy ordinary average people think they are at a much higher risk than they actually are.
Bone density measurementsTechniques Several methods are available to measure bone
density, but currently the most widely used technique is DEXA (Dual Energy Xray Absorptiometry). This is the method used to determine efficacy in the recent large clinical trials, and to characterize fracture risk in large epidemiological studies.
Newer techniques such as ultrasound appear to offer a more cost-effective method of screening bone mass. Ultrasound measurements are usually performed at the calcaneous and it is not possible to measure sites of osteoporotic fracture such as the hip or spine.
Bone density measurements Quantitative computed tomography of the spine
must be done following strict protocols in laboratories that do these tests frequently; in community settings the reproducibility is poor. The QCT measurements decrease more rapidly with aging, so the "T scores" in older individuals will be much lower than DEXA measurements.
Several other techniques can measure bone density at the hand, radius or ankle. These include single energy absorptiometry, metacarpal width or density from hand xrays. Magnetic resonance imaging is a new method of measuring bone density.
T & Z scores and the WHO definitions The WHO has based definitions on the T-score,
which is the number of standard deviations from the mean (average) value of a 25-year-old woman.
1. Normal bone: T-score better than -1. 2. Osteopenia: T-score between -1 and -2.5 3. Osteoporosis: T-score less than -2.5 4. Established osteoporosis includes the presence of
a non-traumatic fracture. One standard deviation is at the 16th percentile, so by definition 16% of young women have osteopenia!
The Z-score is the number of standard deviations below age-matched avereage.
Bone density measurements
DEXA reports Step 1: the images Step 2 - the graphs Step 3 - the basic results Step 4 - the reference ranges Beware the shifting reference ranges!
Comparing a recent scan to one done prior to about 1997.
Step 5 - the areas and mineral contents
Bone Mineral Apparent Density BMAD is important when measuring bone density
in children or in patients with short stature. Another term for this concept is "volumetric bone density".
The DEXA technique analyzes the attenuation of xrays as they pass through an area of the body. The method cannot detect the depth of the bone which is being measured, and thus is actually an "areal" density in g/cm2 rather than a "volumetric" or Archemdean density in g/cm3. As bones grow, the volume increases at a faster rate than the area, so the areal bone density will increase even if the volumetric density remains stable.
Standardization of BMD and Reproducibility
The three manufacturers of DEXA equipment do not give STANDARDIZED RESULTS. The differences are clinically important, making it difficult to compare a measurement made from one machine to the other.
Studies frequently report reproducibility of DEXA between 1 and 2%. This is the average precision; the range is rarely reported. But repeat measurements may show as much as 7% difference.
Biochemical markers of bone cell activity
BIOCHEMICAL MARKERS OF BONE RESORPTION
NTX Aminoterminal cross-linking telopeptide of bone collagen Collagen-based
CTX Carboxyterminal cross-linking telopeptide of bone collagen Collagen-based
PYD Pyridinoline Collagen-based
DPD Free Lysyl-pyridinoline (deoxypyridinoline) Collagen-based
TRACP Tartrate-resistant acid phosphatase Secreted by osteoclasts
Hyp Hydroxy-proline (not very specific) Collagen-based
Biochemical markers of bone cell activity
BIOCHEMICAL MARKERS OF BONE FORMATION
Bone ALP, BAP Bone-specific alkaline phosphatase
Secreted by osteoblasts
PICP Procollagen type I C propeptide Collagen-based
PINP Procollagen type I N propeptide Collagen-based
OC Osteocalcin (bone gla-protein) Secreted by osteoblasts
ALP Alkaline phosphatase (not very specific) Secreted by
osteoblasts
Biochemical markers of bone cell activity
The biochemcial markers of bone formation and bone resorption are frequently called markers of "bone turnover." It is better to remember specifically which process is being measured, because sometimes the bone formation and resorption are not linked (for example, in steroid-induced osteoporosis, bone formation is low but bone resorption is high).
These markers can NOT BE USED TO DIAGNOSE OSTEOPOROSIS! They help us understand the physiology of bone disease, especially in groups of patients or in clinical trials. For individual patients, the markers are of limited use and not recommended for screening or routine follow-up. They do provide information which can help decisions in complex cases.
Diagnosis of osteoroposis (T & Z scores and the WHO definitions)
Differential diagnosis Remember that not all fractures are osteoporotic. The differential diagnosis of fractures includes:
Trauma, Pathologic fracture from neoplasm, Osteomalacia, Paget's disease, Infections (such as TB), Fibrous dysplasia, Peripheral neuropathy, "March" fractures from repetitive stress
Many of these may be diagnosed from radiographs, bone scans, or magnetic resonance imaging studies. Sometimes bone biopsies are necessary.
Diagnosis and differential diagnosis
Physical finding Patients with decreased bone density usually have no
specific abnormal physical findings. Those with vertebral compression fractures will have kyphosis, protruding abdomen and height loss. Back tenderness is usually only present after an acute fracture. Gait speed and grip strength are often reduced in patients who have or are about to have a hip fracture. Visual acuity should be checked in geriatric patients because it is a risk factor for falling.
Secondary causes of osteoporosis may be associated with physical findings, such as nodular thyroid, hepatic enlargement, cushingoid features, skin rashes, jaundice, abnormal dentition, and findings of hypogonadism.
Diagnosis and differential diagnosis Xray findings Sometimes decreased bone density ("demineralization") can
be detected by xray, but bones can appear normal despite loss of 30% of bone mineral. On the other hand, bones in over-exposed films can appear demineralized when they aren't. Bone density measurements are much more accurate than xrays in determining bone density.
The "Singh index" of the proximal femur correlates with bone density. The trabeculae of the femur are lost in sequence, depending on the physical stresses to the bone, so the remaining trabecular pattern indicates the severity of bone loss.
Fractures are discussed in the clinical description page.
Break 10 minutes
Prevention and Treatment
Basic prevention Calcium Vitamin D Exercise Fall prevention Nutrition and weight gain Stop smoking When to add medications
Prevention and Treatment
Calcium to treat and prevent osteoporosis Recommendations Calcium intake of 1 to 1.5 g/day Calcium content of foods Forms of calcium and Dietary factors Some practical information about calcium Mechanisms of action It is probably through inhibition
of PTH secretion and effects of the calcium receptor. Studies relating calcium intake to bone density A
study of calcium in men and women older than 65 showed that dietary calcium and vitamin D supplementation moderately reduced bone loss and reduced the incidence of nonvertebral fractures.
Side effects
Prevention and Treatment
Vitamin D metabolism It is formed in the skin after exposure to
ultraviolet radiation and also is absorbed from the diet. It is hydroxylated at the liver to 25-hydroxyvitamin D, and in the
kidney to 1,25-dihydroxyvitamin D which is the active form. levels Measure 25(OH) vitamin D, not 1,25(OH)2 vitamin D
supplementsnatural sunlight and fortification of dietary foods, particulary dairy products and some cereals.
Active Metabolites
Disorders of vitamin D
Prevention and Treatment
Exercise Physical activity I recommend walking for prevention of hip
fractures. Back extension exercises and Tai Chi also are beneficial.
Interventions in premenopausal, postmenopausal and elderly women
Physical therapy Specific exercises Skeletal response to mechanical forces
Prevention and Treatment Fall Prevention The risk factors for falls include: use of sedatives, previous fall, cognitive
impairment, visual impairment, lower-extremity disability, foot problems, gait abnormalities
At home, elderly or frail people should: keep bathroom lights on, install grab bars, avoid
loose rugs, remove clutter, keep wires behind furniture
gait training or balance training
Prevention and Treatment Hip Protection Thin women have less fat and soft tissue around the hips,
and if they fall the full impact is transferred to the bone. Padding using materials that absorb the energy can
significantly reduce the risk of hip fracture.
Smoking cigarettes Cigarette smoking contributes to osteoporosis, as well as a
host of other medical conditions. Perhaps concern about osteoporosis will be the final thing that will convince patients to stop smoking.
The studies show negative effects of cigarette smoking on the bone. One longitudinal study of 116,229 female nurses found the age-adjusted relative risk for hip fracture was 1.3 in current smokers. Ten years after smoking cessation, the risk was reduced.
Pharmaceutical treatment of osteoporosis Physicians must pay attention to basic prevention
before writing a prescription. Medications do not work as well (if at all) in patients who have poor nutrition, vitamin D deficiency, or lack of exercise. Patients with secondary osteoporosis may require different
treatments from those that are useful for primary OS. ESTABLISHED TREATMENT OF ESTABLISHED
OSTEOPOROSIS
Estrogen , Calcitonin , SERMs , Bisphosphonates , Intermittent PTH
EXPERIMENTAL THERAPIES
Combinations, Fluoride, Growth Hormone, Active Vitamin D, Other ALGORITHMS
Women aged 50-60 , Women aged 60-80 , Women older than 80
Estrogen INDICATIONS
* Prevention of osteoporosis: in early postmenopausal women with low bone density *Treatment of menopausal symptoms
CONTRA-INDICATIONS * Pregnancy * Breast cancer * History of thrombophlebitis without trauma * Active hepatitis * Severe hypertriglyeridemia
USE WITH CAUTION * Lupus * Endometriosis * May need to adjust doses of thyroid or coumadin * Coronary Artery Disease (don't start estrogen)
Estrogen SIDE EFFECTS
Negative effects Positive effects
Short-term Breast tenderness, Vaginal bleeding Reduce hot flashes
or spotting Enlarge fibroids, Migraine headaches, Less gain of abdominal fat
Abdominal bloating, Nausea, Skin rashes, Increase Increase HDL cholesterol triglycerides, Coronary artery disease (with progestin) Decrease LDL cholesterol
Thrombophlebitis, Stroke Helps vaginal atrophy
Long-term Gall stones, Fewer osteoporotic fractures Breast cancer (especially with progestin), Decrease risk of colon cancer
Endometrial cancer (if no progestin) Improves pelvic musculature
Prevents collagen loss in skin (fewer wrinkles) Questionable effects on Alzheimer's disease
Estrogen
Decisions about estrogen must be made on an individual basis.
The recommendation is to use low to moderate doses of estrogen in women within ten years of menopause who have low bone density (bottom 20% of population, T-score lower than -1.6) but are otherwise healthy.
In older women, estrogen is effective for preventing fractures, but it is not the first choice medicine because of side effects on the heart or strokes. Women who have already decided to use estrogen for other
symptoms will be getting good bone protection.
Dose and route of administration A recent study of estratabs showed dose-response between 0.3 and
1.2 mg/d in perimenopausal women. Other forms and routes of administration appear to give similar results in terms of bone density.
Estrogen
When to start estrogen Epidemiological studies have suggested that the
maximum prevention of fractures occurs in women who started estrogen within 5 years of menopause.
In older women, estrogen increases bone density as well as bisphosphonates, and estrogen prevents fractures. However, as discussed above, there is a greater risk of starting estrogen in women who are more than ten years past menopause. Therefore, it would not be a first choice medication for osteoporosis in older women.
Estrogen Studies showing beneficial effect on
bone density Many physicians do not realize that
estrogen improves the bone density as well or better than alendronate. This is a randomized study in women younger than 60. Randomized studies in older women show similar changes in bone density between estrogen and alendronate.
Estrogen Other effects of estrogen CARDIOVASCULAR AND LIPID
1. estrogens increase HDL and decrease LDL-C
2. estrogen has been shown to have beneficial effects on the development of arteriosclerotic plaques in the coronary arteries, which were independent of the effects on the lipids.
ENDOMETRIAL CANCER THROMBOPHLEBITIS OTHER EFFECTS
1. The risk of gallstones doubles.
2. Estrogens help to delay the loss of skin collagen and beneficial to the skin.
3. Estrogen is the only effective treatment for vasomotor instability associated with menopause. It also is used to treat vaginal atrophy.
4. There is a lower incidence of AD in women who take estrogen.
5. Contrary to popular opinion, estrogens do not cause weight gain.
What about progesterone? Progestins have been given to women who still
have a uterus, because estrogen alone can increase the chance of endometrial cancer. But there are increased risk of breast cancer and heart disease in women taking combination hormone therapy.
The abstracts at the 2001 ASBMR have shown increased bone density with medroxyprogesterone acetate and norethindrone, when added to estrogen.
Progestins have several side effects, including bloating and depression. The beneficial effects of estrogen on the serum lipids are reduced with progestins.
Calcitonin Calcitonin: produced by cells in the thyroid
gland, acts directly on osteoclasts (via receptors on the surface). The osteoclasts shrink and stop bone resorption. Bone biopsies from patients treated with the drug show no effects on mineralization.
Indications: Prevention of vertebral compression fractures
Dose: Nasal spray/im, 200 units/day Side effects: Minor adverse effects are seen in
a small number of patients. Calcitonin does not reduce the serum calcium levels in patients with postmenopausal osteoporosis. This natural hormone has been in clinical use for many years with a very good safety profile.
Biphosphonates The bisphosphonates are very powerful, they cause
dramatic changes in the bone physiology, and they deserve respect. In patients with a high risk of fractures, these medicines reduce the incidence of fractures and improve the quality of life.
The vast advertising in medical and public media has increased the awareness of osteoporosis and possiblity of treatment, which is good, but also has led many people and physicians to think the drugs are very safe.
The results from women in their 70's are assumed to apply to young women, without consideration of potential long-term effects. Until we know more about the effect of long-term suppression of bone formation rates, these drugs should be used carefully.
Biphosphonates
INDICATIONS: Postmenopausal women with vertebral compression fractures or with total hip bone density below 650 mg/cm2 (T-2.5) , Elderly men with non-traumatic fractures , Some patients with secondary osteoporosis due to corticosteroids , Paget's disease , Cancer metastatic to bone, Other bone diseases with high bone resorption
CONTRA-INDICATIONS: Women who are pregnant or planning pregnancy, Renal insufficiency, Low serum calcium, Osteomalacia; Oral bisphosphonates should not be used in: Patients with serious esophageal disease and at bedrest who can't stay upright for 1hour
USE WITH CAUTION: Patients with abnormal white blood cells , Patients with high PTH , Children (no long-term safety data)
Biphosphonates
SIDE EFFECTS All bisphosphonates: Hypocalcemia,
Increased PTH, Skin rashOral forms: Upper GI irritation, Esophageal
ulceration Intravenous forms: Fever, Transient
leukopenia, Acute-phase reaction, Bone pain, Eye inflammation, Nephrotic syndrome
Etidronate (Didronel): Osteomalacia, Hyperphosphatemia
Biphosphonates
PHYSIOLOGIC EFFECTS Decreased bone resorption Decreased bone formation by 70-95% Increased mineralization density Slight increase in bone volume Increase bone strength first 5 years Decreased fracture rate first 5 years Half-life in bone greater than 10 years Increased micro-damage in animals Long-term effects on bone unknown
Biphosphonates
Dose for fracture prevention The fracture rates with the lower doses was not significantly
different from the rates in higher doses, despite greater increases in the DEXA measurements with the higher doses.
The FIT trial of alendronate documented significant fracture reduction at 2 years with the 5mg/day dose. After 2 years the dose was increased to 10mg/day, but the study design precluded actual dose comparisons.
Subsequent studies have shown that doses given once a week are as effective as those given daily. Almost all patients prefer this approach, so that is what I ususally use.
In general, we give the lowest dose necessary to achieve a benefit. Why the exception with the bisphosphonates? I think it is because too many people rely on the surrogate measurement (DEXA) instead of the important endpoint of fracture reduction.
Mechanisms of actionPossible cellular actions of bisphosphonates Interfere with osteoclast cytoskeleton Inhibit mevalonate pathway enzymes Decrease protein-tyrosine phosphatases Stimulate apoptosis of osteoclasts Inhibit osteoclast attachment to bone Inhibit proton pump of osteoclasts Inhibit secretion of matrix metalloproteinases Act on osteoblasts to inhibit stimulator of osteoclast
recruitment Act on osteoblast to stimulate inhibitor of osteoclast
recruitment Act on osteoblasts to inhibit osteoclast activity
Intermittent PTH Brands: Parathyroid hormone is naturally
produced as an 84-amino-acid polypeptide. There have been some studies with various forms of PTH. The FDA has approved recombinant PTH 1-34, with a new chemical name of teriparatide made by Lilly with the brand name Forteo.
Dose: The only dose is 20 mcg/day, given by intermittent subcutaneous injection once a day using a special injection device. At this time the duration of treatment should not exceed 2 years.
Indications: I think that 1-34 PTH will be a useful addition to osteoporosis treatment. PTH had demonstrated low bone formation rates and low resorption rates, and the patients continue to have fractures despite other osteoporosis therapy.
Intermittent PTH
Contra-indications:
Children and adolescents, Persons who have had bone cancer, Persons who have had radiation therapy involving the bones, Patients with Paget's disease, Patients with hypercalcemia, Women who are pregnant or nursing, Patients with active gout
Side effects :
Nausea in 8% (similar to placebo), Headache in 8%, Dizziness in 9%, Leg cramps in 3%, Hypercalcemia in 11% (usually mild but a few patients needed to stop PTH), Uric acid increased by 13%
Intermittent PTH Physiological actionsPTH stimulates osteoblastic activity,
especially on trabecular surfaces. It also stimulated osteoclastic activity. PTH will cause more increase in bone
formation than in bone resorption. Micro-array analysis has shown that
different genes are expressed in bone cells that have been exposed to continuous PTH than those expressed after intermittent PTH
SERMs (Selective Estrogen Receptor Modulators)
raloxifene (Evista) SERMS are "designer" estrogen-related
medications that activate the estrogen receptors, but have different effects on different tissues.
There are two kinds of estrogen receptors, and after binding to receptors, the drug-receptor complex can have various conformations.
Some of these will act like estrogen, others will inhibit the actions of estrogen.
Raloxifene is a newer SERM that has been approved for prevention and treatment of postmenopausal osteoporosis.
Raloxifen Dose: 60mg/day. Indications: Treatment and prevention of
postmenopausal osteoporosis. Contra-indications: Premenopausal women, Men,
Women who have had thrombophlebitis Effects on fracture rates: The medication inhibits bone
resorption. Biochemical markers of bone resorption and formation decrease, and bone density increases.
The MORE study enrolled 7705 postmenopausal women who had osteoporosis defined by a bone density T-score of -2.5 or lower or a vertebral compression fracture. The results for vertebral fractures were significant, but there was not a significant decrease in the non-vertebral fractures.
Side effects: flu, hot flashes, leg cramps, diabetes
Raloxifen
Important other effects and non-effects There is no increased incidence of vaginal bleeding or
endometrial pathology. The lipid profile is more favorable, with decreases in the
LDL cholesterol. In the MORE study there was no significant difference in
cardiovascular endpoints. It is a good choice for women who have osteoporosis and
do not want to take estrogen because they are concerned about breast cancer. It doesn’t suppress the bone formation rate as much as the bisphosphontes, and it doesn’t deposit in the bone, so on a physiological basis it should be a safer drug to use for many years.
Experimental therapies Combinations: The ideal combination would be an
antiresorptive medication combined with one that enhances osteoblast function.
Thiazides Fluoride :Fluoride definitely increased the bone formation rate as well as the bone density. However, osteomalacia still resulted.
Growth Hormone Statins Other Really experimental
End of Presentation
The important thing to remember is
that being diagnosed with osteoporosis
is not the end of world. With a careful
treatment program that may include
doctor-supervised exercise, a healthy
lifestyle, and possibly medication, even
fragile bones have the chance to gain
strength.
