BISPHOSPHONATES VS. NUTRITION FOR OSTEOPOROSIS?

A SENSIBLE APPROACH

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The antiresorptive agents, bisphosphonates, have become the most commonly used pharmaceuticals for the treatment of osteoporosis. Most physicians and millions of patients who have taken bisphosphonates view them as harmless drugs that increase bone mineral density and reduce the risk of fractures. But after decades of use, concerns are now rising over the safety of bisphosphonates.

HOW DO BISPHOSPHONATES WORK?

Bisphosphonates are synthetic analogs of inorganic pyrophosphates that bind to the divalent calcium ion (Ca2+) in the hydroxyapaitite crystal of bone. It is here that nitrogen-containing bisphosphonates are able to decrease osteoclast activity and survival. They do so by repressing farnesyl diphosphate synthase, an enzyme in the mevalonate pathway that is important for the synthesis of osteoclast cell regulatory proteins. Without these proteins, osteoclasts can no longer function and bone resorption is substantially reduced. With decreased osteoclastic activity, resorption sites are reduced, which lessens the risk that a minor external mechanical load could impart a breakpoint strain leading to trabecular buckling and catastrophic structural failure. It is from this reduction in resorption sites that bisphosphonates are able to reduce fractures. The increase in bone mineral density seen with these drugs is only weakly associated to their ability to reduce fractures. From a glance, and from statistics showing that bisphosphonates reduce both vertebral and nonvertebral fractures, this seems a very positive therapeutic outcome: but there are drawbacks to these powerful drugs that must be considered before prescribing their use.

WHAT ARE THE SIDE EFFECTS OF BISPHOSPHONATE USE?

As with any medication, there can be both minor and major side effects. The most common minor disturbances of oral bisphosphonate use are stomach pain, bone and joint pain, diarrhea, gas, indigestion, and nausea. Intravenous bisphosphonates can cause transient fever, muscle pain, uveitis, optic neuritis, and injection-site thrombophlebitis. Of the more concerning side effects with oral bisphosphonate use, esophagitis is the most common. Gastric ulcerations can be severe and are not infrequent, but the most alarming complication is osteonecrosis of the jaw (ONJ). Although most commonly seen in cancer patients receiving intravenous bisphosphonates (1-10 per 100 patients), ONJ is also seen in osteoporosis patients taking oral bisphosphonates. The exposed jawbone of the ONJ patient is usually resistant to treatment, can become infected, and leads to chronic intractable pain and disfigurement. Discontinuing bisphosphonates after the diagnosis of ONJ does not seem to improve its response to therapy, which remains supportive at best.

Measures are available that may help prevent bisphosphonate-associated ONJ. The patient needs to optimize dental hygiene. Salivary pH, the microflora of the mouth and gut, and bodily tissue repair factors all contribute to oral health. Also, through monitoring bone turnover biomarkers such as N-telopeptide and bone-specific alkaline phosphatase, we may be able to use “drug holidays” to cycle the use of biosposphonates, thereby reducing the risk of oversuppressing osteoclastic activity and bone turnover.

MICROFRACTURE RISK FROM LONG-TERM BISPHOSPHONATE USE?

Bisphosphonates interrupt the tightly coupled bone-renewing synchrony of osteoclasts that get rid of the old, worn, microfractured bone and the osteoblasts that form strong renewed bone. This reduction in bone turnover leads to skeletal ageing, and there are concerns that long-term bisphosphonate use (> 3 years) may lead to brittle bones and an increase in microfractures. This brittleness is due to altered mineralization properties such as a rise in mineralization homogeneity, which is not a feature of normal healthy bone.

In addition to altered mineralization from long-term use of bisphosphonates, adverse changes also occur within the bone’s nonmineral organic matrix, specifically within the collagen fibers. The “material properties” of collagen give it its strength, and this, in part, is dependent upon the formation through enzymatic mechanisms of structural cross-linking. These enzymatic cross-links hold the collagen fibers together and give them strength and also impart flexibility and toughness to bone. When cross-links are formed from non-enzymatic sources, such as through advanced glycation end products (AGEs) seen with chronic elevation of blood glucose in diabetes or in chronic oxidative stress, collagen integrity is sacrificed, bone becomes more brittle, and fracture risk increases. Bisphosphonate therapy, with reduced osteoclastic activity and bone turnover, leads to the accumulation of these non-enzymatic cross-links and may be of great concern to patients using bisphosphonates long term, especially those, such as diabetics, who are most susceptible to the formation of AGEs.

The extent to which these property changes, induced by long-term bisphosphonate use, influence fracture risk is, as yet, unresolved. But one can easily foresee that ageing bone, especially in a young individual who started taking bisphosphonates when he or she was 30, 40, or even 50 years old, may not end up as “healthy” bone.

WHAT IS THE MOST SERIOUS POTENTIAL CONSEQUENCE OF BISPHOSPHONATE USE?

Concerns over the side effects from bisphosphonate use are obvious and valid. But serious side effects are relatively rare and they pale in comparison to another potentially devastating drawback from the unscrutinized, premature use of bisphosphonates for the treatment of osteoporosis. That is the failure to therapeutically address the chronic inflammation and metabolic dysfunction that is often not only the major underlying cause of bone loss but may also be a potential contributor to other disease processes not yet manifested. By using bisphosphonates to improve bone density, only one aspect of osteoporosis is being addressed. The underlying inflammation, a consistent contributor to all chronic degenerative disease processes, continues untreated.

Strategic nutritional therapy can reduce a patient’s fracture risk without the risks for adverse effects posed by drug therapy. It therefore makes clinical sense to first use nutritional therapy before resorting to pharmaceuticals. There are, of course, situations where a patient may have already sustained one or more fragility fractures or has been determined to be in imminent fracture risk and may require a combination of drug (such as teriparatide, the 1-34 amino acid segment of parathyroid hormone) and nutritional therapy. But in the clinical setting, there is often a window of time where the use of nutritional therapy can be used as a first choice.

Specific biomarkers shown to be related to bone health can be used to identify metabolic dysfunction that can be improved through nutrition. In addition, because osteoporosis is a catabolic disease with high correlation to diabetes, Alzheimer’s, and cardiovascular disease, improving these indicators may reduce etiopathologic mechanisms of other disease processes. Drug therapy as a first choice does nothing to improve a person’s overall health. It can only reduce fracture risk and that only possibly for a limited time period.

WHAT FACTORS MUST BE CONSIDERED PRIOR TO PRESCRIBING A BISPHOSPHONATE?

All too often, physicians look at improving bone density with a bisphosphonate as being the means to an end, when in fact the bone loss is just one symptom within a system struggling against a catabolic tide of inflammation-induced destructive forces. Before a person is placed on bisphosphonates as a panacea for bone loss, many factors should and must be ruled out. These include vitamins D and K deficiency, hypercalcemia, mineral deficiencies, high oxidative stress, chronic systemic inflammation, chronic low-level metabolic acidosis, malabsorption syndromes such as celiac disease, food allergens leading to chronic systemic inflammation, and heavy-metal toxicity. Artificially increasing bone density with a bisphosphonate while leaving the catabolic fires of destruction to burn on is both shortsighted and irresponsible.

Assessing an individual’s true fracture risk has been difficult until recently when the World Health Organization (WHO) made available a new tool called FRAX, or the fracture risk assessment tool. This Web-based tool helps doctors predict the ten-year fracture risk for those who have been diagnosed with osteoporosis. An individual’s risk factors such as age, sex, weight, height, and femoral neck BMD, if available, as well as clinical risk factors are entered into the online tool. The FRAX^® algorithm then provides a figure that indicates a ten-year fracture probability as a percentage. In addition to the FRAX, we can also use laboratory tests to improve our assessment of risk and guide the application of a nutritional treatment program. These lab values include the resorption markers N-telopeptide and deoxypyridinoline, but other indirect markers such as morning urine pH, urine organic acids, chemistry screen, CBC, 24-hour urine calcium, TSH, anti-tissue transglutaminase, antigliadin antibodies, glucose, 25-hydroxyvitamin D, homocysteine, hsCRP, and others can also be used to assess fracture risk and overall health. When biomarkers are abnormal, they may reflect a rise in the patient’s risk for fracture. Prescribing a bisphosphonate before laboratory tests are obtained is not an optimal approach to improving a patient’s bone health.

In summary, when bisphosphonates are used before adequate laboratory evaluation and before appropriate strategic nutrition is used to reduce fracture risk, we have lost not only an important opportunity to normalize bone remodeling but a chance to reduce the catabolic forces of chronic inflammation and further disease.

Basic Multicellular Unit (BMU)

A BMU is the worksite where osteoclasts are busily tearing down old, worn bone and the osteoblasts are coming along right behind to form new bone, which is then hardened with crystalline mineral salts (hydroxyapatite) to give it strength. This remodeling process is graphically depicted in the diagram. At any one moment, millions of BMUs within our skeletal system are actively making strong new bone in an effort to eliminate microfractured areas that result from the wear and tear of normal daily living.

Catabolic vs. Anabolic

A number of important physiological conditions must be present for BMUs to function optimally. For bone to grow and remodel, there must be balance within the endocrine and immune systems, and good communication between bone cells. Vitamins, minerals, and protein must be available in sufficient quantities, as well as a healthy digestive system from which they can be absorbed. Finally, for proper enzymatic function and mineral homeostasis, the body needs a fairly neutral pH. When all these elements are present, we have an “anabolic environment—a healing atmosphere where there can be a positive state of tissue-building activity. If, on the other hand, the body harbors low-level, chronic inflammation, has a struggling immune system, or severe pH imbalance, then bone formation will lag behind bone resorption with the overall effect of bone tissue loss. This undesirable condition is known as a “catabolic” environment—a destructive atmosphere where the metabolic system is severely compromised. And osteoporosis is the classic catabolic state.

Medication

Unfortunately, bisphosphonate therapy has become the current osteoporosis treatment of choice. Bisphosphonates (Fosamax, Boniva, among others) do nothing to put the body into an anabolic state, and they actually eliminate the remodeling process. Bisphosphonates destroy osteoclasts, thereby stopping resorption and the stimulation of osteoblastic new bone formation. And these medications carry their own risks. They have the potential to increase fractures later in life, and they can have dangerous side effects including osteonecrosis of the jaw (ONJ). The hope of reducing fracture risk through improved density with bisphosphonates is sometimes overly optimistic. (Click here for more information on bisphosphonates.)

If, instead, we use diet and nutrition to optimize the whole body’s function and to moderate factors involved in the remodeling process, bone quality can be improved naturally. This should be the first line of treatment. Unlike some other diseases, osteoporosis is chronic and slow moving, and there is usually time, if caught early enough, to try a natural method for improving your bone density. Each person is unique, and the decision to approach low bone density through diet and supplemental support, or through drug intervention, or a combination of the two must be made on an individual basis and with the help of your physician.

Nutritional Support

Based on physical signs and symptoms and on information gathered from standard laboratory tests, called biomarkers, Dr. McCormick helps his patients set up a treatment program that will modify their lifestyle and diet and will probably include supplemental nutrition in order to help the whole physiology. In most cases, bone loss is just one symptom of a greater story of ill health—one that must be approached through a sophisticated, evidence-based platform.

To understand how nutritional support can help, let’s look again at the biology of bone tissue. The communication system between bone cells is a series of linked stimuli and responses. Problems in bone biology arise when signals are either blocked or amplified. If signals are muffled or slowed, or if they are inappropriately amplified, the balance between the remodeling cells (osteoclasts and osteoblasts) falters and both bone density and quality are lost. The molecules that conduct this communication system are cytokines, growth factors, and glycoproteins. These molecules are all woven throughout a bone’s collagen foundation, and they orchestrate the periods of active remodeling.

The molecules we will look at here are the cytokines. These proteins are veritable multitaskers that are involved in many different functions throughout the body. Cytokines stimulate or inhibit cascades of biochemical interactions that affect the bone-remodeling process. They are also actively involved in the body’s immune response to injury. This response is inflammation. No matter where an inflammatory response originates—autoimmune problems, toxic gut, glucose imbalances, oxidative stress—the immune system’s response will always be the same; it will flood the body with a deluge of specific cytokines that add to the total inflammatory response. These are called “pro-inflammatory” cytokines, and they are the reason for the intimate relationship between the immune system and the health of our bones. Some of the same pro-inflammatory cytokines that are involved in immune reactions are also involved in bone resorption. Cytokines such as interleukin-1 (Il-1), interleukin-6 (Il-6), and tumor necrosis factor (TNF) are all pro-inflammatory cytokines involved in the excessive loss of bone tissue.

Sometimes learning about bone biology can be overwhelming, but if there were only one molecule whose name was important to remember, it would be “receptor activator nuclear kappa-B ligand,” or RANKL for short. RANKL stimulates increased osteoclastic bone resorption, and if we are concerned about osteoporosis, then we want to decrease the effects of RANKL. Excess RANKL is caused by two factors—an overabundance of pro-inflammatory cytokines from chronic, low-level inflammation, and a struggling immune system; this unhealthy combination will result in excessive bone loss. Abnormal levels of pro-inflammatory cytokines and RANKL can be lessened by changing your diet and adding to it specific nutritional supplements.

Improving bone density and reducing the risk for fracture requires more than just increasing your intake of calcium, vitamin D, and maintaining a good weight-bearing exercise program. Dr. McCormick’s goal is to optimize key physiological functions and reduce excess production of pro-inflammatory cytokines and RANKL, thereby improving your bone quantity, quality, and strength. Most of the nutritional supplements he might prescribe are available for purchase at the front desk.

Discovering why someone has excessive bone loss is not simple—nor is improving his or her structural soundness. Osteoporosis is a complex polygenic disease with multiple pathogenic mechanisms, but Dr. McCormick uses many diagnostic tools to track its insidious effects. Much can be done to improve the health and strength of your bones, but it takes teamwork, financial commitment, and patience. Nutritional supportive therapy requires effort and attention, but it is a direct path to whole body wellness; this would include, of course, your bones.