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Rheumors Volume 5, Number 1: Winter 1994

OSTEOPOROSIS
by Norman S. Koval, M.D.

Osteoporosis is a disease process in which the density of bone is decreased to a level so low that it is prone to fracture. Unfortunately, this can often be the first signal that the disease is present. More than 24 million Americans, 80% of whom are women, suffer from this debilitating disease. It is a major public health problem which results in expenditures in excess of 10 billion dollars annually. It is estimated that the annual price tag for the treatment of osteoporosis within the next 30 years will increase to between 30 and 60 billion dollars.

From the time that our bones are first formed they undergo "remodeling", a process in which old bone tissue is broken down or reabsorbed and new bone tissue is formed. Bone is constantly remodeling. It is not an inert substance. New bone is formed at a rate greater than the reabsorption process during the first 30 to 35 years of life. At age 30 to 35, however, bone formation and bone reabsorption are about the same. At this time, bone has reached its peak mass. After age 35, bone reabsorption activity increases and in the years prior to menopause there is a gradual decrease in density. At the menopause, when estrogen (the female hormone produced by the ovaries) levels decline, an accelerated loss of bone occurs which may result in the clinical condition we call osteoporosis.

The cause of osteoporosis remains unclear. We do know that there are certain risk factors:

1. sex - women are at a 4 times greater risk of developing osteoporosis than men,
2. age - the risk of osteoporosis increases with age,
3. calcium deficiency - calcium is necessary to help in achieving peak bone mass,
4. race - Caucasians are at greater risk,
5. sedentary lifestyle - regular physical activity is known to increase bone mass,
6. body size, petite women are generally more prone to this disorder than larger framed females. Heavier women may be at less risk because fat cells are a site for estrogen production,
7. family history - there is an increased incidence in families of having osteoporosis although a specific genetic connection has never been discovered,
8. cigarettes/alcohol - cigarette smoking as well as alcohol intake reduce the body's ability to absorb calcium, thereby, negatively affecting bone density, and
9. medications - certain long term use of medications such as corticosteroids, anti-seizure drugs and thyroid hormone can interfere with calcium absorption..

Consequence of Osteoporosis: The most devastating consequence of osteoporosis is bone fracture, usually occurring in either the spine, hip or wrist. There are two types of bone - cortical (compact bone) and trabecular (spongy bone). Cortical bone forms the outer shell of bone and trabecular bone comprises the interior of bone. The "long bones" of the body (the arms and legs) contain greater concentrations of cortical bone while the "flat bones" (spine and hip) contain a greater concentration of trabecular bone. The trabecular bone density is lost at a much more rapid rate at menopause. Since the back bones are comprised of a high concentration of trabecular bone they are common sites for postmenopausal fractures. These fractures can produce the condition of the Dowager's hump which is a loss of height and bent-over posture, causing the protrusion of the abdomen (pot-belly), difficulty in breathing and pain. As the subject reaches the late 60's and 70's there is an increase of hip fractures. Statistics compiled by the National Osteoporosis Foundation report that a woman's risk of developing a hip fracture is equal to her risk of developing breast, uterine and ovarian cancer combined. Hip fractures may often be deadly. Twenty percent of individuals who survive a hip fracture will die within the first year. Of those individuals who survive a hip fracture, only 25 to 50% maintain their previous level of physical functioning and up to 30% may become totally dependent on others for the activities of daily living.

Making a diagnosis of osteoporosis depends upon the physician having a high index of suspicion, knowing who has risk factors for osteoporosis, and knowing that there are techniques for diagnosing this disorder before fractures occur. Presently, the most sensitive test available for making this diagnosis is known as dual energy x-ray absorptiometry (DEXA). This offers a highly accurate measurement of the hip and spine with a very low dose of radiation exposure. The exposure is one-tenth of the radiation level of a standard chest xray.

The most important treatment for osteoporosis is actually prevention. Education of the female in her teenage years to appropriate diet and exercise is paramount in the prevention approach. Estrogen replacement therapy, calcium supplementation, proper exercise regimen, bisphosphonates, Calcitonin and several investigational agents still early in their development, such as growth hormone and parathyroid hormone, may be used in the treatment of this disease. Medical treatments for this disorder will be discussed by the other contributors to this edition of Rheumors.

The physicians of Arthritis & Rheumatism Associates are dedicated to the education of patients, and physicians alike, as to the gravity of this major public health problem.

QUESTION & ANSWERS SECTION

Rheuminations

INCLUSION CRITERIA FOR ENTRY INTO A NEW BISPHOSPHONATE ORAL AGENT OSTEOPOROSIS STUDY

We are currently enrolling patients in an osteoporosis third generation bisphosphonate study. Inclusion criteria follows:

1. Female, at least 5 years post menopausal, either artificial or natural.
2. Be less than or equal to 85 years of age.
3. Meet xray requirements, two or more vertebral deformities or one deformity with low bone mineral density.
4. Be ambulatory.
5. Be able to and willing to participate in the Study as evidenced by having signed an informed consent

If you meet these criteria and are interested in entering our study, contact Donna at the osteoporosis office at 949-1134 or June in our main office at 593-9100.

Points on Joints

BISPHOSPHONATES
Herbert S. B. Baraf, M.D.

Of all the new drug therapies for osteoporosis, none holds more promise than that held by a class of agents called BISPHOSPHONATES. The first of these, Etidronate, was originally developed as a water softener and was used to prevent soap scum. By a stroke of good fortune however, Etidronate was found to have significant medical usefulness. Etidronate, marketed under the trade name Didronel, is one of six different bisphosphonate compounds that are of clinical interest in osteoporosis. Thus far, however, none of these drugs has received FDA approval for osteoporosis treatment.

Presently there are only two bisphosphonates available for clinical use in the United States; Etidronate and Pamidronate. Etidronate was initially approved by the FDA more than 15 years ago for the treatment of Paget's Disease, a sometimes serious and fairly rare bone disorder. Pamidronate was made available this year to cancer patients because of its ability to lower elevated serum calcium levels resulting from their cancer's effect on bone. Four additional agents are currently being evaluated in clinical trials. All six of these drugs are actively being studied for their effectiveness in osteoporosis treatment. Thus far, all seem to have promise. Etidronate (Didronel) is the first of the bisphosphonates to be studied in osteoporosis. It is referred to as a "first generation" agent. It differs from most of the -2- others in its dual ability to inhibit resorption of calcium from bone and deposition of calcium into bone. Of course, in treating osteoporosis only this first effect is desirable. Fortunately, Etidronate is a weaker inhibitor of calcium deposition than it is of calcium resorption. When used for osteoporosis therapy however, it must be given for short periods and then withheld for longer periods so as to selectively inhibit resorption without inhibiting new bone formation.

Pamidronate and tiludronate are among the "second generation" bisphosphonates. Risedronate is a "third generation". Unlike Etidronate, these drugs are more selective in their effect on bone, only demonstrating significant inhibition of bone resorption. They can therefore be given on a more continuous basis.

Etidronate (Didronel), among all of the bisphosphonate compounds, has been studied the longest. Several multicenter studies with this agent have been ongoing and have shown significant improvement in bone density for as long as five years into therapy. Fractures related to osteoporosis seem to occur with less frequency in treated patients. Side effects have been minimal and the drug has been well tolerated. In addition, Etidronate has been shown to inhibit bone loss in patients who require long term cortisone (steroid) treatment. Studies with other bisphosphonates are hoped to show at least the same degree of improvement.

Thus, a number of new drugs, all in the bisphosphonate class, are under development for the prevention and treatment of osteoporosis. These drugs hold considerable promise because of their low toxicity, moderate effectiveness and their ease of administration. As compared to female hormones (which cannot be given to male osteoporosis patients and have significant side effects for some women) and calcitonin, which is very expensive and must be given by injection, bisphosphonates show some clear advantages.

Once again, a discovery aimed at a mundane task such as eliminating the ring around your bathtub has led to a major medical breakthrough - an important treatment for osteoporosis.

Rheuminations

CALCITONIN
by Emma DiIorio, M.D.

Osteoporosis is a condition in which a person's bone mass decreases, leaving these bones more susceptible to fracture. We can reduce one's risk of osteoporotic fractures by increasing bone mineral density and by preventing bone loss. This can be achieved with various substances. One of these substances is calcitonin.

Calcitonin is a hormone that is made and secreted by the thyroid gland. Calcitonin prevents bone resorbing cells, known as osteoclasts, from resorbing bone. Calcium levels in the blood control calcitonin release, so that the intake of dietary calcium increases calcitonin production and decreases bone resorption.

Synthetic salmon calcitonin is 40-50 times more potent than human calcitonin. Clinical studies using calcitonin in the treatment of osteoporosis have shown effective responses, ranging from slowing of further bone loss to a striking increase in bone mass. At present the only route of administration approved in the United States is by subcutaneous injection (similar to insulin administration). Intranasal administration is currently undergoing clinical trials in the United States. To see if you are a candidate for this treatment, your physician will obtain a baseline measurement of your bone mass. Once treatment has begun, annual measurements of bone mass are done to see if the drug has been effective in either increasing bone mass or preventing further bone loss.

Calcitonin is also as effective as estrogens in preventing bone loss in postmenopausal women. It can easily serve as an alternative in the prevention of osteoporosis in women who are unable or unwilling to take estrogens.

Beyond its beneficial effects on bone mass, calcitonin has analgesic effects. It provides pain relief to patients with acute osteoporotic fractures. The analgesic effects begin within a few weeks of the start of treatment.

Calcitonin is a relatively innocuous medication. The most common side effects are nausea, vomiting, gastric discomfort, metallic taste, facial flushing, and skin hypersensitivity. Most of these symptoms decrease or disappear with continued use. It is best to administer the drug at bedtime and to take Benadryl thirty minutes before injection to decrease gastrointestinal side effects.

In summary, calcitonin is the treatment of choice in patients with severe osteoporosis, especially in patients with osteoporotic fractures and in steroid related osteoporosis. It also serves as an alternative to estrogen therapy and is effective in the prevention of osteoporosis.

Rheuminations

DEFLAZACORT
by Emma DiIorio, M.D.

Steroid medications such as Prednisone are used for the treatment of a variety of disorders including rheumatoid arthritis and polymyalgia rheumatica. Steroid medications have many adverse effects, including hypertension, diabetes, cataracts, and cause significant loss of calcium from bone, leading to osteoporosis.

Deflazacort, a new derivative of Prednisone, is thought to cause less of this troublesome bone loss and yet be as effective as Prednisone. We are currently conducting a two-year randomized double blind study comparing Prednisone to Deflazacort in patients with rheumatoid arthritis and polymyalgia rheumatica. The primary goal of this study is to confirm the relative bone-sparing effect of Deflazacort. We are actively enrolling patients with established rheumatoid arthritis or polymyalgia rheumatica currently on Prednisone, or in whom the initiation of Prednisone is being contemplated.