Osteoporosis Protocol

Treatment of Osteoporosis with Bisphosphonates
Another class of agents used to treat osteoporosis are bisphosphonates, which are essentially bone-rebuilding drugs. These include: alendronate (Fosamax), tiludronate (Skelid), pamidronate (Aredia), etidronate (Didronel), risedronate (Actonel), and zoledronic acid (Zometa). Bisphosphonates work primarily by decreasing calcium resorption (bone breakdown). The net result is an increase in bone mineral density (BMD) and a reduced risk of fractures (Greenspan et al. 2000; Fleisch 1997). German researchers, who reviewed a number of studies, concluded that, "From systematic research the best external evidence is available for a supplementation with calcium and vitamin D and a therapy with the bisphosphonates alendronate or risedronate, as well as the selective estrogen receptor modulator raloxifene (Evista)"(Minne et al. 2002).

To date, many studies have shown that bisphosphonates are effective for treating osteoporosis and preventing it in high-risk groups, particularly postmenopausal women. At the University of Heidelberg, Germany, bisphosphonates have been shown to prevent vertebral fractures in osteoporotic patients and reduce the incidence of new fractures of the femoral neck in those with preexisting fractures. The authors write that, "The introduction of bisphosphonates into the treatment of osteoporosis is definitely an enrichment of the therapeutic spectrum in conjunction with the basic treatment comprising calcium, vitamin D, diet, and physical measures" (Wuster et al. 1997).

The two bisphosphonates, etidronate and alendronate, for example, have been proven to increase bone mass and decrease fracture incidence at the spine, hip,

Table 1: Bisphosphonate Drugs
Name Generic Name Dosage
Fosamax* Alendronate 10 mg a day or 70 mg a week
Actonel* Risedronate 5 mg a day
Aredia Pamidronate (IV injection) 30-90 mg a month
Zometa Ibandronate and Zolendronic acid (IV injectipj) 4 mg a year
Skelid Tiludronate 400 mg a day
Didronel Etidronate 5 mg a day
The bisphosphonate drugs listed above have a narrow range of safety and must be prescribed by a knowledgeable physician.
*Actonel and Fosamax are the only bisphosphonate drugs that are presently approved in the United States for the treatment of osteoporosis.

and other sites by 50% compared to control rates in postmenopausal women (Russell et al. 1999). Meanwhile, researchers in New Zealand reported similar results following a 2-year randomized, double-blind, placebo-controlled study of pamidronate (150 mg a day) in 48 postmenopausal women with osteoporosis. Findings showed that the bone mineral density, which was measured at 6-month intervals, revealed a progressive increase in the entire body at all skeletal sites, although no significant changes occurred in the placebo group. There were nearly twice as many fractures per year occurring in the placebo group (24 per 100) than in the pamidronate group (13 per 100) (Reid et al. 1994). Also, a South American study found that 100 mg daily of oral pamidronate in postmenopausal women with confirmed osteoporosis resulted in a lowered rate of height loss and significantly lower incidence of total number of new fractures and new hip fractures (Man et al. 1997).

In larger experiments, such as the Vertebral Efficacy with Risedronate Therapy (VERT) study, investigators looked at 2458 women under 85 with postmenopausal osteoporosis and at least one vertebral fracture. Subjects were randomly assigned to oral risedronate 2.5 or 5 mg a day or placebo for 3 years. All received 1000 mg calcium a day, and those with low vitamin D levels received up to 500 IU a day. The 3-year, 5-mg treatment decreased the cumulative incidence of new vertebral fractures by 41% and invertebral fractures by 39%. Bone mineral density increased significantly, compared with placebo, at the lumbar spine (5.4% versus 1.1%), femoral neck (1.6% versus 1.2%) and at other measured sites (Harris et al. 1999).

The most definitive data regarding postmenopausal women comes from the United States-based Fracture Intervention Trial (FIT), the largest osteoporosis clinical trial to date involving more than 6000 women aged 54-81. Researchers examined the effect of daily alendronate in 2027 women with vertebral compression fractures over a 3-year period and in 4432 without fractures over a 4-year period. In the group with existing fractures, they found that alendronate increased bone mineral density by 8% at the spine and 5% at the hip, while decreasing the incidence of all clinical fractures from 18.2% in placebo to 13.6% in the treated group, and vertebral compressions decreased from 15% to 8% (Black et al. 1996). However, differences were not significant between the test and placebo group in the branch of the study looking at women without baseline fractures (Cummings et al. 1998). All participants reporting calcium intakes of 1000 mg a day or less received a supplement containing 500 mg of calcium and 250 IU of vitamin D. Subjects were randomly assigned to either placebo or 5 mg a day of alendronate sodium for 2 years, changing to 10 mg a day for the remainder of the trial. Results showed that alendronate increased bone mineral density at all sites studied and reduced clinical fractures from 312 in the placebo group to 272 in the intervention group, although not significantly (14%).

Studies have also demonstrated that bisphosphonates are effective for osteoporosis resulting from secondary or unknown causes. For example, in cancer patients, bisphosphonates are standard treatment for hypercalcemia of malignancy (HCM), a skeletal complication that affects more than 10% of all cancer patients, and 20-40% of advanced cancer cases. It is especially common in patients with bone metastases, and those with breast and prostate cancer account for about 80% of bone metastases. Overstimulated osteoclasts result in an increased rate of bone resorption, causing bone weakening, while excess calcium makes its way into the bloodstream and creates complications, such as dehydration, fatigue, nausea, vomiting, confusion, and coma (Diel et al. 2000).

In a Belgian study, researchers gave 26 patients with either age-related or glucocorticoid-induced osteoporosis 60 mg of pamidronate intravenously every 3 months for 1 year. Researchers found that after only 3 months of treatment, patients' pain scores, due to chronic back pain from osteoporotic vertebral fractures, fell from 3.2 to 1.2 in both osteoporotic groups (Gangji et al. 1999). Meanwhile, Australian researchers suggest that, based on medical literature, postmenopausal women receiving corticosteroids should be given bisphosphonates, vitamin D metabolite, or hormone replacement (in that order) to prevent or reverse associated bone loss (Sambrook 2002).

In Denmark, researchers examined the effect of 10 mg daily of alendronate on lumbar spine bone mineral density in 32 patients with low bone mineral density, due to complications from Crohn's disease, for 12 months. Bone density increased by 4.6% in the lumbar spine and 3.3% in the hip in the alendronate group, respectively, compared to a decrease of 0.9% and 0.7% at the same sites in the placebo group. Authors concluded that 10 mg daily of alendronate increased bone mineral density in patients with Crohn's disease and was safe and well tolerated (Haderslev et al. 2000).

Likewise, in liver disease and liver transplant patients, for whom osteoporosis is a common complication, giving intravenous bisphosphonates (pamidronate) preoperatively prevented fractures in high-risk patients. Patients were treated with pamidronate every 3 months, before surgery and for 9 months afterward and were compared to an untreated group. None of those receiving bisphosphonate therapy (0 out of 13) suffered postoperative fracture, whereas 31% of those who went untreated did (Reeves et al. 1998).

Possible Mechanisms
Researchers know that bisphosphonates have an incredible affinity for bone, binding to calcium and building up in the mineralized bone matrix, so that it is more resistant to breakdown by osteoclasts. Still, it is not perfectly clear how they work. It is suspected that bisphosphonates affect signaling between osteoblasts and osteoclasts. Some in vitro studies have suggested that bisphosphonates may initiate macrophage death, thereby also overcoming their deleterious effects on osteoblasts. Macrophages are found on osteoblasts and are thought to have some responsibility for excessive bone resorption, namely by impeding the activity and survival of osteoblasts. Researchers found that adding bisphosphonates to cocultures of osteoblasts and macrophages blocked the adverse effects of macrophages on osteoblasts. Bisphosphonates increased the number of osteoblasts by 82% and reduced the number of macrophages. Also, control cocultures revealed fewer osteoblasts than the treated ones (Evans 2002).

Because of various modes of action observed in studies, bisphosphonates have been classified into two groups. Bisphosphonates that closely resemble pyrophosphate--a normal byproduct of human metabolism (such as clodronate and etidronate)--are incorporated into adenosine triphosphate (ATP) analogues, which create compounds that are believed to build up and lead to osteoclast death (Martin et al. 2000). The newest generation of bisphosphonates, which contain nitrogen (such as pamidronate, alendronate, risedronate, and ibandronate), are believed to inhibit protein prenylation (post-translational modification) within the mevalonate pathway. The mevalonate pathway is responsible for the biosynthesis of cholesterol, other sterols, and isoprenoid lipids. Isoprenoid lipids are key in the prenylation of intracellular signaling proteins (GTPases) that, when activated, regulate a number of processes, including osteoclast activity. It is believed that by impeding the function of these regulatory proteins, bisphosphonates result in blocking osteoclast functioning and causing apoptosis (Wuster et al. 1997 ).

Weighing Pros & Cons
Besides attempting to unravel how bisphosphonates work, researchers are also aiming to address their benefits and risks. The fact that bisphosphonates bind so strongly to bone and confine their activity to the skeleton has made clinicians confident about their safety profile. The positive aspect of bisphosphonates is that, because their effects are limited to bones, adverse effects elsewhere in other body tissues and organs are minimal (Fleisch 1997). However, thanks to their antiresorptive properties, bisphosphonates have been accused of substantially reducing bone turnover, in turn, impairing microdamage repair and causing increased bone mineralization, which can increase bone fragility. Thus, it is important to weigh how "osteoporosis therapies may also affect bone architecture by causing the redistribution of bone structure. Restructuring of bone during treatment may change bone fragility, even in the absence of drug effects on bone mineral density (BMD)" (Thiebaud et al. 1994).

Bisphosphonates also have some side effects, regardless of their narrow target of action. The most commonly reported side effects of oral bisphosphonates are gastrointestinal complications, such as esophagitis, gastritis, and diarrhea (Turner 2002). Intravenous delivery of bisphosphonates is being examined as a way to sidestep gastrointestinal adverse effects for those who cannot tolerate oral bisphosphonates, as well as a strategy to reduce dosing frequency significantly. There are adverse effects related to IV administration too, such as iritis (inflammatory eye disorder), muscle aches, and fever (Greenspan et al. 2000).

More Research
Studies are attempting to elucidate how bisphosphonates work best, the question focusing on delivery modes (oral versus IV), dosing amount and frequency. While some research has looked at intermittent dosing, given every few weeks or months, the latest findings reported in the New England Journal of Medicine suggest that just one annual injection of the bisphosphonate, Zometa (zoledronic acid), boosts bone mineral density as well as more frequently dosed oral bisphosphonates (Reid et al. 2002). In the study led by a New Zealand team of scientists, 351 postmenopausal women with low bone mineral density were randomized into five different treatment regimen groups: 0.25 mg, 0.5 mg, or 1 mg given every 3 months; a 2-mg dose every 6 months; a single 4-mg dose; or an inactive placebo. Increases in bone mineral density were reported among all Zometa-treated patients, which were comparable to increases associated with a daily regimen of any of the three oral bisphosphonates: Actonel, Fosamax, and Aredia. Larger studies with a 5-mg dose of Zometa are underway, one involving over 8000 men and postmenopausal women with osteoporosis, while another includes about 3000 men and postmenopausal women.

Another question being investigated is whether bisphosphonates are preferable to other treatments for the purpose of preventive therapy in high-risk groups. Some studies have debated whether bisphosphonate therapy is appropriate for patients under 60 with osteopenia (low bone density) without fractures. Generally, bisphosphonates have been indicated for individuals who have established osteoporosis or who are at high risk of the disease. A large British study called the Early Postmenopausal Intervention Cohort Study Group weighed bisphophonates against hormone replacement therapy (HRT). Investigators looked at the effect of 2.5 mg versus 5 mg of alendronate a day or placebo on bone mineral density in 1174 postmenopausal women under the age of 60. Also, 435 more women were randomized to receive alendronate, a placebo, or combination estrogen-progestin therapy. Results showed that controls lost bone mineral density at all measured sites. Contrarily, women receiving 5 mg of alendronate daily had an average increase in bone mineral density of 3.5% at the lumbar spine, 1.9% at the hip, and 0.7% for the total body. Women treated with 2.5 mg of alendronate daily had smaller increases in bone mineral density. And the estrogen-progestin combination showed a 1-2% better response rate than a 5-mg dose of alendronate (Hosking et al. 1998). While the study's authors concluded that bisphosphonates were comparable to hormone replacement therapy, others argue that HRT is still the best mode of preventive therapy in postmenopausal women because of additional beneficial effects on other organ systems, and not just bones (Ravn 2002).

Finally, researchers are still delving further into the question of how appropriate bisphosphonates are for treating osteoporosis in men, as the majority of studies have focused on women. It remains to be seen whether they work as well in men as they do in women, although clinical experience would suggest that is the case. Also, some research now indicates that bisphosphonates positively affect bone mineral density in men with idiopathic or secondary osteoporosis (American Society for Bone and Mineral Research 1998; Heilberg et al. 1998). Preliminary data from a large placebo-controlled trial of alendronate in men with osteoporosis also suggests a positive effect on bone mineral density (Anderson et al. 1997).

Osteoporosis and MEN

It is important for men to utilize the same nutritional guidelines as women. Attention to testosterone level is especially important. DHEA and melatonin may be helpful in men as well. In some cases consideration for the use of some progesterone should be made. Lastly, the importance of exercise cannot be overemphasized. Supplemental DHEA is contraindicated in both men and women with certain hormone-related cancers (refer to the DHEA Replacement Therapy protocol and Male Hormone Modulation Therapyprotocol for more information).

Toxins

There is ample evidence that fluoride found in drinking water and toothpaste may contribute to bone destruction (Turner et al. 1992, 1997; Sogaard et al. 1995). The use of properly filtered water and toothpaste without fluoride is recommended.

Suppressing Pro-inflammatory Cytokines

As people age, they often produce excess levels of inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1b (IL-1b), and tumor necrosis factor alpha (TNF- a ) (James et al. 1997; Brod 2000). Cytokines are immune system-regulating chemicals. Pro-inflammatory cytokines (such as IL-6) can induce a chronic state of systemic inflammation and damage the bone matrix.

Dietary supplements such as the DHA fraction of fish oil, vitamin K, and DHEA can suppress dangerously high levels of pro-inflammatory cytokines. IL-6, in particular, has been linked to bone loss. Vitamin K, fish oil (Burke et al. 1997), and DHEA have demonstrated efficacy against osteoporosis (Haden et al. 2000). It would appear that these supplements might function via several mechanisms to protect against bone loss.

Conclusions and Recommendations

In summary, there are a variety of solutions to the problem of osteoporosis. Whatever choices you make should be made in consultation with your family doctor or a specialist and may require changes in lifestyle and diet, plus or minus hormone replacement or other supplemental or drug therapy. It is critical to address these issues, however, because osteoporosis is both preventable and treatable.

In order to help you make decisions about what particular treatment would be best for you, the following schematic may be useful.

SUMMARY

The following nutrients, hormones, and drugs should be considered in the prevention and treatment of osteoporosis:

Proper nutritional supplementation with vitamins and minerals, in particular calcium. Six capsules a day of Bone Assure provide the ideal dosages and forms of calcium, magnesium, zinc, manganese, and vitamin D3, boron and other nutrients to protect bone density.
Weight-bearing exercise may help increase bone density.
Supplemental hormones such as DHEA, 25-50 mg a day and melatonin, 300 mcg-3 mg each night should be considered by both men and women.
Vitamin K in the dose of 10 mg a day facilitates the formation of a bone-building protein and dramatically reduces fracture risk. Do not take vitamin K if you are taking coumadin or some other type of anticoagulant medication. For treatment, take up to 45 mg a day under the supervision of a physician who monitors blood coagulation factors.
Soy extract may improve bone density and bone mineral content, 55-110 mg of active isoflavones (genistein, daidzein, and glycitein) each day.
Consider bisphosphonate drug therapy if there is any evidence of a loss of bone mineral density as measured by a QCT test.
Application of natural progesterone cream may stabilize or improve bone density. Follow dosage directions in this protocol.
Men should pay particular attention to testosterone replacement therapy (refer to the Male Hormone Modulation protocol for details).
Ipriflavone may suppress bone resorption, 300 mg a day.
Avoid red meat and switch to fish as a protein alternative. Using a supplement called Super GLA/DHA (provides gamma linolenic acid from borage oil and DHA from fish oil) is the best documented way of suppressing excess levels of proinflammatory cytokines, such as interleukin-6 (IL-6) that break down bone.
Readers are referred to the Female Hormone Replacement Therapy protocol for additional information regarding estrogen and progesterone therapy.
Note: QCT bone density measurements and Pyrilinks-D urine tests should be performed to assess bone density status.
For more information

Contact the National Osteoporosis Foundation, (800) 223-9994.

Osteoporosis Protocol Pg (1) (2) (3)

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