Osteoporosis Prevention and Treatment Protocol
In contrast with conventional medicine’s reactive, after-the-fact approach to osteoporosis, Life Extension recommends a comprehensive, integrative strategy to address all of the underlying causes and exacerbating factors involved in osteoporosis. Like most chronic conditions, prevention of osteoporosis is a much better choice than treatment.
Bioidential Hormone Replacement Therapy
Considering the importance of estrogen, progesterone and testosterone on bone health, Life Extension urges its members to regularly obtain a complete hormone profile. Conventional hormone replacement therapy (Premarin® and Provera®) provides hormones that are unnatural to the human body. Bioidentical hormones, on the other hand, have the same exact molecular structure as the hormones produced naturally within the body. As a result, bio-identical hormones are properly utilized, and are then able to be naturally metabolized and excreted from the body. The use of bioidentical HRT has increased during the last several years as women have sought out a more natural approach to restoring hormonal balance. Generally overlooked by mainstream medicine are research findings suggesting that women may more safely benefit from individualized doses of natural estrogens and progesterone.
Estriol (a type of bioidentical estrogen), has been documented for increasing bone mineral density. A Japanese study involving 75 postmenopausal women found that after 50 weeks of treatment with 2 mg/day of estriol cyclically and 800 mg/day of calcium lactate, women had an increase in bone mineral density with no increased risk of endometrial hyperplasia (uterine tissue overgrowth that may precede cancer) (Minaquchi, 1996). In a second study emanating from Japan, researchers treated postmenopausal and elderly women with 2 mg/day of estriol and 1,000 mg/day of calcium lactate versus 1,000 mg/day calcium lactate alone. Bone mineral density significantly increased in women who received estriol, while the women who did not take estriol experienced a decrease in bone mineral density (Nishibe A, 1996).
Similar research has confirmed these findings. In this investigation, 25 postmenopausal women were given either 2 mg/day of estriol plus 2 gram/day of calcium lactate, or 2 grams/day of calcium lactate alone for one year. Bone mineral density was significantly reduced in the group that received calcium alone (without estriol). In contrast, the group that received estriol plus calcium experienced a 1.66% increase in bone mineral density after one year. Furthermore, biochemical markers of bone resorption were significantly decreased in the estriol group. “These data indicate that the acceleration of bone turnover usually observed after menopause was prevented by treatment with E3 [estriol],” the authors of this study noted (Nozaki, 1996).
A 2009 study compared the effects of conventional hormone replacement (conjugated equine estrogens and medroxyprogesterone) to that of estriol in 34 postmenopausal women. After one year of treatment, bone mineral density as well as lipids were measured. In both groups bone mineral density showed improvement however, women taking conventional HRT had an increase in triglycerides that was not seen in the women taking bioidentical estriol. The authors concluded that estriol might be an efficacious alternative to conventional HRT (Kika, 2009).
Given the degree of evidence, maturing women should understand that bioidentical hormone replacement, when appropriately prescribed, offers an alternative to conventional hormone replacement to help relieve menopausal symptoms and optimize bone density, and that accumulating evidence suggests that bioidentical hormone replacement appears to offer advantages over conventional hormone replacement therapy.
Hormonal balance is critical for maintaining optimal bone metabolism and overall health. In addition to restoring estrogen, testosterone, and progesterone levels to youthful ranges, DHEA levels should also be maintained. DHEA is a hormone that is active throughout the body; it also serves as a precursor to testosterone and estrogen. Indeed, some evidence suggests that DHEA supplementation may support bone health in aging women (Weiss 2009; von Muhlen 2008).
Note: For more information on bioidentical hormone replacement, please see the Female Hormone Restoration protocol.
Isoflavones, chiefly derived from soybeans, chemically resemble estrogen; as a result they are often referred to as phytoestrogens – literally, plant estrogens (Morabito 2002). Following the worrisome safety issues associated with the Women’s Health Initiative showing increased cancer risk in women on synthetic hormone replacement therapy (HRT), there has been dramatically increased interest in phytoestrogens as an alternative.
The primary soy isoflavones (in order of abundance) are genistein, daidzein, and glycitein; all three have confirmed phytoestrogenic effects (Anderson 1999). Genistein and daidzein have been shown in animal and human studies to contribute to increased bone mineralization and bone strength, while reducing bone resorption (Harkness 2004, Newton 2006, Weaver 2009, Sehmisch 2010). A 2002 study showed that genistein supplementation (54 mg/day) reduced urinary markers of bone turnover in a fashion similar to conventional HRT (Morabito 2002). The same study demonstrated increased serum markers of bone protein formation in genistein recipients; HRT recipients actually showed decreased levels of those proteins. And animal studies show that genistein reduces bone resorption by a mechanism different from the bisphosphonate drugs and estrogen (Lee 2004). Finally, the phytoestrogen isoflavones have substantial anti-inflammatory effect, adding to their ability to break the chain of events that contribute to osteoporosis (Ji 2011).
Concerns have been raised about the possible effects of phytoestrogens on breast cancer risk, given their biochemical similarity to estrogen (Marini 2008). Long-term studies, however, have demonstrated no increased risk of cancer or precancerous changes in women taking 54 mg/day of genistein (Marini 2008). In fact, “consumption of genistein in the diet has been linked to decreased rates of metastatic cancer in a number of population-based studies. Extensive investigations have been performed to determine the molecular mechanisms underlying genistein's antimetastatic activity, with results indicating that this small molecule has significant inhibitory activity at nearly every step of the metastatic cascade” (Pavese 2010).
A total daily isoflavone dose of about 54-110 mg for preventing loss of bone mineral content and reducing markers of bone resorption appears reasonable based upon the literature (Uesugi 2002, Harkness 2004, Atteritano 2009).
Vitamin K regulates several biochemical processes that require exquisite balance to function normally, including blood coagulation, bone mineralization and vascular health. Through the diverse actions vitamin K holds promise in helping to prevent and manage some of the most crippling conditions associated with advancing age, including osteoporosis, coronary artery disease, and blood clots.
Vitamin K is an essential co-factor for building the protein matrix that traps calcium crystals in bone (Sogabe 2011, Rejnmark 2006). Like vitamin D, vitamin K is also essential for preventing calcium accumulation in arterial walls (Okura 2010). People with lower levels of vitamin K are at increased risk for calcification of major arteries (Okura 2010). Vitamin K also reduces activity of bone-resorbing cells by decreasing levels of inflammation regulating complexes (Morishita 2008). Low vitamin K status and use of warfarin-like anticoagulants (which antagonize the action of vitamin K by undermining a process called carboxylation) are associated with low bone mineral density and increased fracture risk (Rezaieyazdi 2009, Binkley 2009). Vitamin K2 supplementation (1,500 mcg/day) has been shown to accelerate proper bone protein formation (Koitaya 2009).
Vitamin K comes in two main forms, K1 (phylloquinone), and K2 (menatetrenone, or M4). Vitamin K2 has been shown to support bone health when used as a supplement in humans (Binkley 2009, Bunyaratavej 2009, Sato 2002).
Vitamin K2 supplementation reduces the amount of circulating bone protein, a measure of inadequate bone formation (Yasui 2006, Shiraki 2009). Supplementation also increases bone mineral content and bone strength at many different body sites, although DEXA scans may or may not show improvement in bone mineral density (Knapen 2007). K2 supplementation added to bisphosphonate drug therapy brings further benefit to both bone mineral density and bone protein (Hirao 2008).
Some individuals with osteoporosis who may benefit from supplementation with vitamin K are also taking warfarin, and so avoid vitamin K because they are concerned that it might interfere with their anticoagulant therapy. However, low-dose vitamin K (100 mcg daily) has been shown to help stabilize the INR (clotting time) of patients on anticoagulant therapy in a small trial (Reese 2005). In fact, emergent research suggests that some the beneficial effects of vitamin K2 for promoting bone mineral density may be entirely unrelated to vitamin K-dependent carboxylation, and resistant to the antagonistic effects of warfarin (Atkins 2009; Rubinacci 2009). Individuals on anticoagulant therapy who are interested in supplementing with vitamin K should discuss low-dose vitamin K with their physicians.
Along with calcium, vitamin D is the nutrient that most people recognize as important for bone health (Holick 2007). But, even today, few people understand the powerful and complex ways that vitamin D acts to promote not only bone health, but the way the entire body handles calcium, both in healthy and in undesirable ways (Holick 2007). Vitamin D triggers absorption of calcium from the intestine and deposition of calcium in bone — and also removal of calcium from blood vessel walls. Conversely, insufficient vitamin D intake results in depletion of calcium from bones — and increased deposition of calcium in arterial walls, contributing to atherosclerosis (Celik 2010, Tremollieres 2010).
Vitamin D deficiency (or insufficiency) also causes muscle weakness and neurological deficits, increasing the risk of falling, which of course makes fractures still more likely (Bischoff-Ferrari 2009, Pfeifer 2009, Janssen 2010). The dose of vitamin D required to achieve the neuroprotective and other non-bone related effects are substantially higher than those required simply to achieve good calcium absorption (Bischoff-Ferrari 2007).
A validated measure of total body vitamin D status in blood is serum 25-hydroxy vitamin D (also known as 25(OH)D, or calcidiol). Note that this measure is reported in two different units, nmol/L and ng/mL, so it is vital to check which set of units a lab is using. Vitamin D deficiency is defined as a serum 25(OH)D level of less than 50 nmol/L, or less than 20 ng/mL. Experts recommend a higher level of 75 nmol/L, or 30 ng/mL (Bischoff-Ferrari 2007, 2009). To obtain the many health benefits of Vitamin D, current scientific evidence suggests a minimum target threshold for optimal health is over 50 ng/ mL or 125 nmol/L (Aloia 2008, Dawson-Hughes 2005, Heaney 2008).
The optimal dose of vitamin D has been hotly debated in recent years. More than 13,000 Life Extension® members have had their vitamin D level checked. The results from these tests provides important information about achieved vitamin D blood levels in a large group of dedicated, health-focused individuals. Vitamin D dosage as high as 5000 to 8000 IU per day may be required to achieve a minimum target level for optimal health in aging individuals (Faloon 2010).
A new study in the journal Anticancer Research echoed Life Extension’s recommendation, noting that traditional intakes of the essential vitamin just aren't enough (Garland 2011), “We found that daily intakes of vitamin D by adults in the range of 4,000 to 8,000 IU [international units] are needed to maintain blood levels of vitamin D metabolites in the range needed to reduce by about half the risk of several diseases -- breast cancer, colon cancer, multiple sclerosis and type 1 diabetes," said the author in a news release about their findings.
Calcium is the predominant mineral in bone, and crystals of calcium compounds give bone its hardness and strength. Most Americans do not meet the daily adequate intake for calcium, so supplementation is generally recommended (Straub 2007). Calcium supplementation also suppresses bone resorption, further fighting osteoporotic changes (Ortolani 2003). Large trials of calcium supplementation, with and without vitamin D, have shown mixed results at preventing osteoporosis, but closer examination of those studies has revealed that many of the patients who got no benefit did not take the supplements regularly (Lips 2009, Nordin 2009, Spangler 2011).
Individuals that are at high risk or that have been diagnosed with osteoporosis may need to consume up to 1,200 mg/day. Calcium supplements are available in many forms. For optimal absorption and convenience of dosing, use a combination of dicalcium malate (DimaCal®), calcium glycinate chelate (TRAACS®), and calcium fructoborate. Calcium citrate is also a water soluble form, and can be taken at any time; it is the supplement of choice for people with suppressed gastric acid secretion, such as those taking antacids and proton pump inhibitors (Straub 2007).
Strontium is chemically akin to calcium, and is taken up by bone cells in an identical fashion (Fonseca 2008, Hamdy 2009). Strontium ranelate, approved in Europe for post-menopausal osteoporosis (Przedlacki 2011), is the first anti osteoporotic medicine that has dual mode of action, simultaneously increasing bone formation and decreasing bone resorption, thus rebalancing bone turnover formation (Delannoy 2002, Fonseca 2008, Cesareo 2010). Strontium ranelate 2g daily has been well studied in postmenopausal women with osteoporosis (Meunier 2004; Reginster 2005; Reginster 2008), significant reductions of up to 43% in the risk of hip fractures were observed over a period of five years (Reginster 2008).
Strontium ranelate has fewer gastrointestinal side effects than bisphosphonates (Fisch 2006). A pooled Phase 3 study did note a slightly increased risk of blood clot (Cortet 2011), therefore anti-thrombotic agents like low-dose aspirin, fish oil, and aged garlic extract should be taken daily if strontium is being used to rebuild bone mass. Those on anti-coagulant or anti-platelet therapy should alert their doctor if they are using strontium. A recent report associated strontium with a form of drug reaction with severe skin breakdown (Le Merlouette 2011).
Strontium ranelate has yet to be approved by the FDA in the United States, however several salts of strontium such as strontium citrate or strontium carbonate are available as dietary supplements, providing close to the recommended strontium element content of strontium ranelate. Little clinical data exists to suggest that other salts of strontium will have the same effects. Despite the lack of clinical evidence, other salts of supplemental strontium are theorized to promote bone health since the cation (strontium element) is responsible for the pharmacological effect of strontium ranelate (Takaoka 2010).
Worth noting, strontium is not an essential mineral (has no known physiological function in human body), dietary strontium is estimated at 2-4 mg/day from vegetables and grains (Nielsen 2004), and the estimated whole-body strontium content of an average (70 kg) human is 320mg (Emsley 1998). Furthermore, the uptake of heavier strontium in place of calcium into bone matrix results in a false increase in bone density as assessed by DEXA scanning, making further follow up of bone density by DEXA harder to interpret (Reginster 2005). Therefore, the pharmacological dose strontium supplements should be reserved for those with significant loss of bone density, and those on supplemental strontium should alert their physicians prior to a bone density test (Nielsen 1999, Reginster 2005).
Magnesium is an important micronutrient that regulates active calcium transport in humans, and is therefore important in bone health (Aydin 2010). Older adults tend to be magnesium deficient because of diminished dietary intake and absorption coupled with increased urinary losses (Barbagallo 2009). Chronically elevated stress hormone levels also contribute to depressed magnesium levels (Barbagallo 2009). Together these effects conspire to damage bone health.
Magnesium supplementation in both animal and human studies reduces bone turnover, tending to favor bone formation over bone resorption (Aydin 2010, Aydin 2010). The resulting improved bone mineralization contributes to a reduction in fracture frequency (Sojka 1995).
Boron is an ultra-trace element that has been discovered to be essential for bone health (Volpe 1993). Its primary effect seems to be its interactions with more prevalent minerals such as calcium and magnesium, but it also has independent anti-inflammatory effects that may contribute to its usefulness (Scorei 2011).
In human studies boron deficiency caused changes in calcium metabolism that resemble those seen in osteoporosis, and which were exacerbated by low magnesium levels (Nielsen 1990). Animal studies show that boron supplementation stimulates bone formation and inhibits bone resorption (Xu 2006).
A daily dose of 3-9 mg of boron from calcium fructoborate, a boron-based supplement which also has antioxidant and anti-inflammatory actions, is reasonable for bone health based upon the scientific literature (Scorei 2005, Scorei 2011).
Silicon is one of the most abundant elements in the Earth’s crust. It has few known biological functions, but recently silica (silicon dioxide) has been discovered to play an important role in bone formation and health (Li 2010). Silicon deficiency in animals results in bone defects (Calomme 2006).
Supplementation with organic silicon compounds, on the other hand, improves bone mineral density and prevents bone loss (Kim 2009, Calomme 2006). A human study demonstrated that the addition of organic silicon to a calcium and vitamin D3 regimen improved production of bone proteins (Spector 2008).
Researchers are now discovering the vital importance of collagen for achieving optimal bone tensile strength. Collagen, a resilient type of protein molecule, makes up most of the structure of bone (Ailinger 2005). The spongy matrix of collagen fibers and crystalline salts within bone is crucial to absorbing compression forces to resist stress fractures, much as the tensile supports of steel bridges provide flexibility so that the bridge can withstand gale force winds and heavy traffic.
Scientists developed a new form of calcium that molecularly binds collagen. This unique form of collagen calcium chelate is designed to enhance collagen support and turnover while increasing bone mineral density and bone strength (AIDP data on file).
Scientists at Tokyo University found that supplementation with collagen calcium chelate improved bone strength to a greater extent than the same amounts of calcium and collagen either given separately or together but in a non-chelated form. Specific improvements with collagen calcium chelate were seen not only in bone mineral density but just as importantly in femur (thigh bone) weight, bone collagen production, and bone flexibility and strength.
In an experimental model of osteoporosis, the test group received a low-calcium diet for one week. In addition to their low-calcium diet, some of the test group consumed a high-dose collagen calcium chelate. The cohort receiving high-dose collagen calcium chelate had an increase in femur bone weight by an impressive 9.6%, compared with the group given the same amount of calcium in non-chelated form. The test group receiving the collagen calcium chelate had dose-dependent increases in bone mineral density, which were 3.5% to 11.1% higher than those seen in the group receiving the same amount of non-chelated calcium. The investigators concluded that collagen calcium chelate had an additive effect on bone mineral density, better than that of calcium alone or of a simple calcium and collagen mixture (AIDP data on file).
Collagen calcium chelate was also associated with increases in femur bone strength, by about 9.9% to 25%, compared with the group receiving the same amount of calcium (AIDP data on file). Remarkably, the benefits of collagen calcium chelate were evident after only eight weeks of supplementation. Given these encouraging results, a large clinical study is currently underway, in collaboration with the US Army, to look at the effect of collagen calcium chelate on bone fractures in hard-training recruits.
Oxidant stress, particularly that imposed by oxidized LDL-cholesterol, is a significant contributor to bone loss in osteoporosis (Zinnuroglu 2011, Mehat 2010). Some bisphosphonate drugs may themselves actually increase oxidant damage as well (Zinnuroglu 2011). Antioxidant vitamins and other supplements, therefore, have an important role in prevention (Chuin 2009, Sugiura 2011).
The antioxidant vitamins C and E play important roles in production of proteins, development of bone-forming cells, and bone mineralization (Zinnuroglu 2011, Hall 1998). Vitamin C also suppresses activity of bone-resorbing cells while promoting maturation of bone-forming cells (Gabbay 2010). Vitamin E improves bone structure, contributing to stronger bone (Shuid 2010).
Women with higher vitamin C intake have significantly better bone mineral density, so long as their calcium intake is also above 500 mg/day (Hall 1998). Postmenopausal women who took 600 mg vitamin E and 1000 mg vitamin C daily achieved stable bone mineral density compared with placebo recipients, whose density dropped over a 6-month period (Chuin 2009). Similar doses of both vitamins were useful in preventing bone loss in elderly men and women (Ruiz-Ramos 2010).
Daily doses of 1000 mg vitamin C, and 600 mg of vitamin E (as mixed tocopherols) are reasonable for osteoporosis prevention; alpha-tocopherol alone is likely to be ineffective (Ruiz-Ramos 2010, Mehat 2010, Chuin 2009, Ima-Nirwana 2004). Recent study investigated the bone anabolic effects of Vitamin E in rats and for the first time reported that gamma isomer improves all the parameters of bone biomechanical strength, while alpha tocopherols only improved some of the parameters (Shuid 2010).
Omega-3 Fatty Acids (Fish and Flax Oils)
The omega-3 fatty acids found in fish oil (EPA and DHA) and flax oil (ALA) have powerful anti-inflammatory and antioxidant effects (Trebble 2004, Fernandes 2008, Maggio 2009). That makes them ideal candidates for inclusion in an anti-osteoporosis regimen, given the role of inflammation in osteoporosis (Trebble 2004). EPA and DHA also reduce activity of bone-resorbing cells, increase that of bone-forming cells, and improve calcium balance (Maggio 2009).
Men and women who consume higher amounts of oily fish (tuna, mackerel, salmon, etc) have greater bone mineral density than do those with lower fish consumption (Farina 2011). Animal studies have shown increased bone mineral content and strength in animals supplemented with fish oils or the omega-3 fatty acids EPA and DHA, as well as the flax seed oil-derived ALA (Sun 2004, Ward 2007, Matsushita 2008, Salari 2008, Sacco 2009). Intriguingly, fish oil plus soy isoflavone supplementation resulted in a higher weight-bearing capacity of lumbar vertebra (Ward 2007).
EPA and DHA have specific anti-resorption effects on bone cells in culture, and also stimulate differentiation and activity of bone-forming cells (Rahman 2008, Rahman 2009). Increased dietary intake of omega-3’s in animals protects against bone loss by down-regulating the important NF-kappa-B inflammation-controlling complex (Fernandes 2008). In human studies, supplementation with EPA (omega-3)and GLA (gamma-linolenic acid-, a beneficial omega-6), along with 600 mg/day of calcium, maintained spine and hip bone mineral density over 18 months, while in placebo recipients bone density fell significantly (Kruger 1998). Fish oil supplements containing a total of 2.7 g/day of EPA and DHA reduced inflammatory cytokine production in humans (Trebble 2004). And daily 900 mg/day of mixed omega-3 fatty acids decreased bone resorption in postmenopausal women with osteoporosis (Salari 2010).
Curcumin is a bio-active component of the Indian spice turmeric (Shishodia 2005). It has powerful antioxidant and anti-inflammatory actions, particularly by reducing the gene expression of the master inflammation-regulatory complex NF-kappa-B (Shishodia 2005, Oh 2008).
Lab studies show that curcumin decreases activity of bone-resorbing cells by reducing NF-kappa-B expression (Oh 2008). Animal studies reveal multiple beneficial effects of curcumin on bone mineral content and structure (Yang 2011). Curcumin improves bone mineral density in rat models of postmenopausal osteoporosis, and increases bone strength (French 2008).
Resveratrol is a powerful phytoalexin molecule produced by plants, especially grape vines and Japanese knotweed, for protection against oxidant stress, and pathogens (Kupisiewicz 2010). As the chief health-promoting component of red wine, it has achieved prominence for its ability to mimic the beneficial effects of calorie restriction on many genes that contribute to longevity and health (Pearson 2008). Among the genes that resveratrol modulates are several that are crucial for bone health.
Certain stem cells can differentiate into either fat or bone tissue, depending on how their genes are regulated. Resveratrol activates genes that tip the cells to develop into bone forming cells, and suppresses those that would create fat cells (Kupisiewicz 2010, Song 2006, Backesjo 2009, Shakibaei 2011). Resveratrol also prevents inflammation-induced maturation of bone resorbing cells (He 2010). In animal studies, resveratrol supplementation results in increased bone mineral density and reduced bone resorption (Liu 2005).
Quercetin is a plant polyphenol found in a wide variety of fruits. It is a powerful antioxidant and a mild phytoestrogen as well (Boots 2008, Wattel 2004). Quercetin directly stimulates the differentiation and activity of bone-forming cells in laboratory studies (Yang 2006, Prouillet 2004). It also reduces activity of bone-resorbing cells through its down-regulation of inflammation (Wattel 2004).
Quercetin recently was shown to enhance activity of the vitamin D receptor in intestinal cells, which in turn helps in proper regulation of calcium metabolism (Inoue 2010). Together these effects provide support for the observation that quercetin supplementation in experimental models inhibits bone loss following induced menopause (Horcajada-Molteni 2000).
Berberine is a plant alkaloid used extensively in ancient Chinese and Japanese medicine for use in promoting bone health (Li 1999, Li 2008). Animal and laboratory studies reveal that berberine prevents decrease in bone mineral density by inhibiting the activities of bone-resorbing cells (Li 1999). Used as a dietary supplement in experimental models, berberine resulted in an increase in bone mineral density (Li 2003). Berberine also increases differentiation of bone-forming cells through activation of cellular signaling pathways (Lee 2008, Xu 2010).
Although berberine has been studied in human clinical trials and shown to have several metabolic benefits, concerns about long-term use of berberine have been raised on the basis of certain preclinical studies (Kysenius 2014; Mikes 1985; Mikes 1983). Some evidence suggests that long-term berberine use, especially at high doses, may impair particular aspects of cellular metabolism in specific types of cells. The implications of this preclinical research are yet to be determined by long-term human clinical trials, therefore Life Extension currently recommends short-term use of berberine.
Hops is an herb best known for producing the typical bitter flavor of beer, and has long been known to have health benefits (Kondo 2004). The active ingredients in hops have multiple biological effects, particularly in their ability to act as selective estrogen receptor modulators (SERMs). In this capacity, hops extracts may boost beneficial estrogen effects without triggering estrogen-related outcomes such as breast cancer (Effenberger 2005). Among their benefits are positive effects on bone mineral density and prevention of osteoporosis (Stevens 2004). Hops extracts increase gene expression and differentiation of bone-forming cells in laboratory studies (Effenberger 2005).