Osteoporosis

Synopsis:
Background
Risk Factors
Nutrients in Preventing & Treating Osteoporosis
Suggested Supplementation
References

Osteoporosis, defined as a reduction of bone mass or bone density, was long viewed as a disease unique to aging women. Sadly, much of what conventional wisdom held true about osteoporosis turns out to be flawed. It is now clear that osteoporosis is not a disease with a singular cause affecting a specific population. Rather, it is a multi-faceted disease driven by a barrage of interrelated factors, and must be addressed as such for optimal prevention and treatment (Clarke 2010).

Today we realize that osteoporosis not only impacts the lives of women, but of men as well; fully one third of those affected by the condition are males. Indeed, one out of every four men will sustain an osteoporotic fracture during their lifetime (Ahmed 2009).

Scientific advancements have revealed that osteoporosis stems not only from hormonal imbalances, but oxidative stress, elevated blood sugar, inflammation, and components of the metabolic syndrome as well (Clarke 2010, Confavreux 2009, Lieben 2009; Zhou 2011).

Overlooked by mainstream medicine is the critical role that micronutrients play in bone health. For instance, emergent research on vitamin K revealed its involvement, along with vitamin D, in both bone health and atherosclerosis, a condition to which osteoporosis is intimately related (Baldini 2005, Abedin 2004). In fact, these two conditions can be thought of as mirror images of one another (McFarlane 2004, D'Amelio 2009). Osteoporosis is characterized by loss of calcium from bones, shifting them from their healthy hard state to a diseased state of softness. Atherosclerosis, on the other hand, is characterized by excessive influx of calcium into arterial walls, shifting them from their healthy flexible state to a diseased state of hardness. Insufficiency of vitamin K contributes to this unhealthy balance.

Another contributor to bone loss in both men and women are advanced glycation end products (AGE’s) – byproducts of high blood sugar. AGE’s interact with proteins in bone causing impaired mineralization, bone breakdown and hardening of the arteries. This relationship between elevated blood sugar, osteoporosis, and atherosclerosis comprises a vicious cycle linking the conditions in a manner unknown to the majority of mainstream physicians (Tanikawa 2009; Franke 2007; Hein 2006; Zhou 2011).

Pharmaceuticals, such as Actonel® or Fosamax®, have shown limited success, and are associated with some potentially serious side effects including atrial fibrillation and osteonecrosis of the jaw (Jager 2003, Howard 2010). These drugs work chiefly by inhibiting the cells responsible for breaking down bone tissue, but neglect multiple other factors responsible for osteoporosis (Roelofs 2010, Varenna 2010).

An integrative approach, based on the human body’s finely tuned relationship with its environment and the nutrients that support bone health, makes much more sense (Confavreux 2009, Hanley 2010). This realization has led to an awakening to the tremendous potential of nutrient and mineral supplements along with hormonal optimization in the prevention and management of osteoporosis.  

 

The Truth about Osteoporosis: Multiple Causes, Multiple Targets

Most of us assume that our bones are like pieces of rocks or hard shells. However, bone is a living tissue, constantly undergoing demolition and renewal as it responds to changing forces in the environment (Martin 2009, Body 2011). Bone is also the body’s primary reservoir of the calcium needed for a wide variety of biological processes (de Baat 2005). Bone is now recognized as an endocrine organ, secreting compounds that function like hormones throughout the body (Kanazawa 2010).

Our bones are made of crystals of calcium salts in a protein matrix. Specific cells, called osteoblasts, produce the matrix and attract calcium compounds to form new bone, while a different set of cells, called osteoclasts, resorbs the bone tissue to allow new shapes and structures to form in response to gravity and the pull of muscles. This process of remodeling helps repair micro-damage that occurs as a result of daily activity and prevents the accumulation of old fragile bone (Martin 2009, Mitchner 2009, Body 2011).  At the simplest level, osteoporosis occurs when more bone is resorbed than formed (Banfi 2010, Chang 2009).

Anyone who is losing height with age may have osteoporosis.  Unfortunately, osteoporosis typically has no symptoms at all until a serious fracture occurs, usually from a relatively minor injury.

 

 

There are many risk factors for osteoporosis and they interact with one another.

• Nutrition status – Suboptimal nutrient intake.
  • Vitamin K – For healthy, mineral-rich bone to form, healthy bone matrix protein must be produced (Bugel 2008, Wada 2007). Over the past decade scientists have realized that vitamin K is an essential co-factor for production of the major bone protein, osteocalcin (Bugel 2008, Iwamoto 2006). Vitamin K-dependent enzymes produce changes in osteocalcin that allow it to tightly bind to the calcium compounds that give bone its incredible strength (Bugel 2008, Wada 2007, Rezaieyazdi 2009).
  • Calcium & Vitamin D – The role of low intake of vitamin D and calcium are well known (Cherniack 2008, Lips 2010). Adequate calcium intake is required to allow healthy bone remodeling and prevent osteoporosis. Vitamin D promotes intestinal absorption of calcium, and also regulates how much calcium enters and leaves bone tissue in response to the body’s other calcium requirements.
  • Trace Minerals – While bone is primarily composed of matrix protein and calcium compounds, small amounts of other trace minerals are essential for normal bone function. These include magnesium, which regulates calcium transport; silicon, which reverses loss of calcium in the urine; and boron, which interacts with other minerals and vitamins and also has anti-inflammatory effects (Aydin 2010 Mizoguchi 2005, Kim 2009, Li 2010, Spector 2008, Scorei 2011).

• Sedentary lifestyle – Lack of weight-bearing exercise. A sedentary lifestyle reduces the constant forces that bone needs to experience in order to continue its normal process of remodeling (Akhter 2010). Studies show that both women and men who engage in regular exercise have much lower risk of osteoporosis and fracture (Ebeling 2004, Englund 2011).

• Gender – Women are more likely to develop osteoporosis than men. This difference is related to several reasons including: the abrupt loss of estrogen at menopause, women start with a lower bone density and lose bone more quickly than men and women live longer than men.

• Age – Increasing age is associated with falling production of estrogen and testosterone, which increases osteoporosis risk. Advancing age also means longer total exposure to chronic oxidant stress and inflammation, both of which contribute to development of osteoporosis (Mundy 2007, Maziere 2010, Seymour 2007, Ruiz-Ramos 2010).  After about the age of 35, the total amount of bone in the body begins to diminish. In women, the process begins fairly sharply with the onset of menopause, when estrogen levels drop dramatically. In postmenopausal women, bone is lost both from the inner and outer surfaces of bones, as bone resorption by osteoclasts exceeds the already reduced new bone formation by osteoblasts. In men, however, new bone formation on the outer surface of bone keeps pace with resorption on the inner surface for much longer (Seeman 1999).

• Ethnicity – Caucasian and South Asian people have greater risk of osteoporosis (Dhanwal 2011, Golden 2009).

• Family History – A family history of hip fracture carries a twofold increased risk of fracture among descendants (Ferrari 2008).

• Estrogen Exposure – Women with late puberty or early menopause are at higher risk due to a decrease in estrogen exposure over their lifetime (Vibert 2008, Sioka 2010). 

• Slim stature (underweight) – People with a body mass index of 19 or less or have small body frames tend to have a higher risk because they may have less bone mass to draw from as they age (El Maghraoui 2010).

• Obesity - Accumulating evidence suggests that obesity-related components such as insulin resistance, hypertension, increased triglycerides, and reduced high-density lipoprotein cholesterol are all risk factors for low bone mineral density (Bredella 2010, Kim 2010).

• Cardiovascular Disease – Cardiovascular disease and mortality are associated with osteoporosis and bone fractures (Baldini 2005). That’s not surprising since the two conditions share many mechanisms and risk factors, such as oxidant damage and inflammation (Baldini 2005, Vermeer 2004).

• Chronic Stress & Depression - Both condition increase cortisol production, leading to suppression of sex hormone production, increased insulin resistance, and enhanced release of inflammatory cytokines (Kiecolt-Glaser 2003, Kaplan 2004, Berga 2005). All of these effects increase the risk of bone mineral loss and osteoporosis (Berga 2005, Bab 2010, Diem 2007, Haney 2007).

• Other risk factors: HIV infection (Ofotokun 2010), anorexia (Mehler 2011), cancer (Ewertz 2011, Lim 2007), smoking (Kanis 2009), caffeine (Tsuang 2006, Tucker 2006), and alcholism (Matsui 2010).

• Medication Use – A variety of medications increase one’s risk for osteoporosis:

Corticosteroids. These immune-suppressive drugs mimic the effect of stress-induced cortisol, with all of its suppression of sex hormones, weight gain, and insulin resistance.

Selective Serotonin Reuptake Inhibitors (SSRIs). Both depression and medications used in its treatment, such as SSRIs, increase the risk of osteoporosis (Bab 2010).

“Blood thinning” Medications (Anticoagulants). The drug Coumadin, used to prevent clot formation in patients with cardiovascular disease, acts to block the beneficial effects of vitamin K and is associated with decreased bone mineralization in some patients (Deruelle 2007). Low molecular weight heparin, an unrelated blood thinner, can also cause reduced bone mineral content (Rezaieyazdi 2009).

• Insulin Resistance, high blood sugar and glycation - Research suggests that advanced glycation end products, or AGEs, are implicated in bone loss. AGEs are formed when proteins interact with glucose molecules to form damaged structures in the body. More AGEs present resulted in fewer bone-building osteoblasts (Hein 2006). It is suggested that limiting AGE formation by maintaining a healthy blood sugar level may slow the osteoporotic process (Valcourt 2007).

• Oxidation and Inflammation – Oxidation of fatty acids and other molecules produces reactive oxygen species that directly and indirectly impair new bone formation and promote excessive bone resorption (Graham 2009, Maziere 2010). In a similar fashion, chronic inflammation hastens the absorption of existing bone while impeding normal production of new bone (Chang 2009). Fat cells produce a steady efflux of inflammatory cytokines while diminishing cells’ insulin sensitivity; both factors further impede normal bone production (Mundy 2007, Kawai 2009).

 

 

Vitamin K

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).

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.

 

Vitamin D

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). 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. 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).

 

Calcium

Calcium is the predominant mineral in bone, and crystals of calcium compounds give bone its hardness and strength. Most people do not meet the daily adequate intake for calcium, so supplementation is generally recommended (Straub 2007).

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

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 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

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

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). 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).

 

Silica

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).

 

Collagen

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.

 

Antioxidant Vitamins

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). 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). 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

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

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

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).

 

Hops

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).

 

 

Effective treatment or prevention of osteoporosis requires commitment to an active lifestyle, and supplementation with targeted vitamins, minerals and nutrients that quench reactive oxygen species (ROS), reduce inflammation, control obesity and insulin resistance, promote healthy bone matrix protein synthesis, and supply sufficient trace minerals to support healthy bone.

Calcium: 1000 – 1200 mg daily

Vitamin D: 2000 – 8000 IU daily (individualize dosing based on results of Vitamin D testing)

Magnesium: 200 – 1000 mg daily

Vitamin K: 2700 mcg daily (as 1500 mcg K1, 1000 mcg MK-4, and 200 mcg MK-7)

Silica: 5 – 10 mg daily

Boron: 3 – 9 mg daily

Zinc: 15 – 30 mg daily

Calcium Collagen Chelate: 3000 mg daily

Omega 3 Fatty Acids: 1400 mg EPA and 1000 mg DHA daily

Curcumin: 400 mg daily

Resveratrol: 250 mg daily

Quercetin: 250 mg daily

 

Abedin M, Tintut Y, Demer LL. Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol. 2004 Jul;24(7):1161-70.

Abrahamsen B. Adverse effects of bisphosphonates. Calcif Tissue Int. 2010 Jun;86(6):421-35.

Adams JS. "Bound" to work: the free hormone hypothesis revisited. Cell. 2005 Sep 9;122(5):647-9.

Adams JE. Quantitative computed tomography. European journal of radiology. Sep 2009;71(3):415-424.

Ahmed LA, Schirmer H, Bjornerem A, Emaus N, Jorgensen L, Stormer J, Joakimsen RM. The gender- and age-specific 10-year and lifetime absolute fracture risk in Tromso, Norway. Eur J Epidemiol. 2009;24(8):441-8. Epub 2009 May 30.

Ailinger RL, Braun MA, Lasus H, Whitt K. Factors influencing osteoporosis knowledge: a community study. J Community Health Nurs. 2005 Fall;22(3):135-42.

Akhter MP, Alvarez GK, Cullen DM, Recker RR. Disuse-related decline in trabecular bone structure. Biomech Model Mechanobiol. 2010 Aug 4.

Akin F, Bastemir M, Alkis E, Kaptanoglu B. SHBG levels correlate with insulin resistance in postmenopausal women. Eur J Intern Med. 2009 Mar;20(2):162-7.

Aloia JF, Patel M, Dimaano R, et al. Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Am J Clin Nutr. 2008 Jun;87(6):1952-8.

Anderson JJ, Anthony MS, Cline JM, Washburn SA, Garner SC. Health potential of soy isoflavones for menopausal women. Public Health Nutr. 1999 Dec;2(4):489-504.

Andreassen TK. The role of plasma-binding proteins in the cellular uptake of lipophilic vitamins and steroids. Horm Metab Res. 2006 Apr;38(4):279-90.

Archer DF. Tissue-selective estrogen complexes: a promising option for the comprehensive management of menopausal symptoms. Drugs Aging. 2010 Jul 1;27(7):533-44.

Atkins G et al. Vitamin K promotes mineralization, osteoblast-to-osteocyte transition, and an anticatabolic phenotype by y-carboxylation-dependent and -independent mechanisms. Am J Physiol Cell Physiol December 2009 vol. 297 no. 6 C1358-C1367

Atteritano M, Mazzaferro S, Frisina A, et al. Genistein effects on quantitative ultrasound parameters and bone mineral density in osteopenic postmenopausal women. Osteoporos Int. 2009 Nov;20(11):1947-54.

Aydin H, Deyneli O, Yavuz D, et al, Short-term oral magnesium supplementation suppresses bone turnover in postmenopausal osteoporotic women. Biol Trace Elem Res. 2010 Feb;133(2):136-43.

Azagra R, Roca G, Encabo G, et al. Prediction of absolute risk of fragility fracture at 10 years in a Spanish population: validation of the WHO FRAX tool in Spain. BMC Musculoskelet Disord. 2011;12:30.

Bab I, Yirmiya R. Depression, selective serotonin reuptake inhibitors, and osteoporosis. Curr Osteoporos Rep. 2010 Dec;8(4):185-91.

Backesjo CM, Li Y, Lindgren U, Haldosen LA. Activation of Sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells. Cells Tissues Organs. 2009;189(1-4):93-7.

Baldini V, Mastropasqua M, Francucci CM, D'Erasmo E. Cardiovascular disease and osteoporosis. J Endocrinol Invest. 2005;28(10 Suppl):69-72.

Banfi G, Lombardi G, Colombini A, Lippi G. Bone metabolism markers in sports medicine. Sports Med. 2010 Aug 1;40(8):697-714.

Barbagallo M, Belvedere M, Dominguez LJ. Magnesium homeostasis and aging. Magnes Res. 2009 Dec;22(4):235-46.

Berga SL, Loucks TL. The diagnosis and treatment of stress-induced anovulation. Minerva Ginecol. 2005 Feb;57(1):45-54.

Binkley N, Harke J, Krueger D, et al. Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women. J Bone Miner Res. 2009 Jun;24(6):983-91.

Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ. 2009;339:b3692.

Bischoff-Ferrari HA. How to select the doses of vitamin D in the management of osteoporosis. Osteoporos Int. 2007 Apr;18(4):401-7.

Body JJ, Bergmann P, Boonen S, et al. Non-pharmacological management of osteoporosis: a consensus of the Belgian Bone Club. Osteoporos Int. 2011 Mar 1. [Epub ahead of print]

Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. 2008 May 13;585(2-3):325-37.

Bredella MA, Torriani M, Ghomi RH, et al. Determinants of bone mineral density in obese premenopausal women. Bone 2011 Apr 1;48(4):748-54.

Bugel S. Vitamin K and bone health in adult humans. Vitam Horm. 2008;78:393-416.

Bunyaratavej N, Kittimanon N, Jitivirai T, Tongthongthip B. Highly recommended dose of MK4 for osteoporosis. J Med Assoc Thai. 2009 Sep;92 Suppl5:S4-6.

Caldwell JD, Jirikowski GF. Sex hormone binding globulin and aging. Horm Metab Res. 2009 Mar; 41(3): 173-82.

Calomme M, Geusens P, Demeester N, et al. Partial prevention of long-term femoral bone loss in aged ovariectomized rats supplemented with choline-stabilized orthosilicic acid. Calcif Tissue Int. 2006 Apr; 78(4):227-32.

Cawthon PM. Gender Differences in Osteoporosis and Fractures. Clin Orthop Relat Res. 2011 Jan 25.

Celik C, Altunkan S, Yildirim MO, Akyuz M. Relationship between decreased bone mineral density and subclinical atherosclerosis in postmenopausal women. Climacteric. 2010 Jun;13(3):254-8.

Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 2008 May-Jun;11(3):343-53.

Cesareo R, Napolitano C, Iozzino M. Strontium ranelate in postmenopausal osteoporosis treatment: a critical appraisal. Int J Womens Health. 2010 Aug 9;2:1-6.

Chanda D, Kumar S, Ponnazhagan S. Therapeutic potential of adult bone marrow-derived mesenchymal stem cells in diseases of the skeleton. J Cell Biochem. 2010 Oct 1;111(2):249-57.

Chang J, Wang Z, Tang E, et al. Inhibition of osteoblastic bone formation by nuclear factor-kappaB. Nat Med. 2009 Jun;15(6):682-9.

Cherniack EP, Levis S, Troen BR. Hypovitaminosis D: a widespread epidemic. Geriatrics. 2008 Apr;63(4): 24-30.

Chuin A, Labonte M, Tessier D, et al. Effect of antioxidants combined to resistance training on BMD in elderly women: a pilot study. Osteoporos Int. 2009 Jul;20(7):1253-8.

Clarke BL, Khosla S. Androgens and bone. Steroids. 2009 Mar;74(3):296-305.

Clarke BL, Khosla S. Physiology of bone loss. Radiol Clin North Am. 2010 May;48(3):483-95.

Clinical Key. First Consult; Osteoporosis. 2013; www.clinicalkey.com. Accessed 10/14/2013.

Confavreux CB, Levine RL, Karsenty G. A paradigm of integrative physiology, the crosstalk between bone and energy metabolisms. Mol Cell Endocrinol. 2009 Oct 30;310(1-2):21-9.

Cortet B. Use of strontium as a treatment method for osteoporosis. Curr Osteoporos Rep. 2011 Mar;9(1): 25-30.

Cutler WB, Friedmann E, Genovese-Stone E. Prevalence of kyphosis in a healthy sample of pre- and postmenopausal women. Am J Phys Med Rehabil. 1993 Aug;72(4):219-25.

D'Amelio P, Isaia G, Isaia GC. The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease. J Endocrinol Invest. 2009;32(4 Suppl):6-9.

Dawson-Hughes B, Heaney RP, Holick MF, et al. Estimates of optimal vitamin D status. Osteoporos Int. 2005 Jul;16(7):713-6.

de Baat P, Heijboer MP, de Baat C. Development, physiology, and cell activity of bone. Ned Tijdschr Tandheelkd. 2005 Jul;112(7):258-63.

de Paula FJ, Horowitz MC, Rosen CJ. Novel insights into the relationship between diabetes and osteoporosis. Diabetes Metab Res Rev. 2010 Nov;26(8):622-30.

Delannoy P, Bazot D, Marie PJ. Long-term treatment with strontium ranelate increases vertebral bone mass without deleterious effect in mice. Metabolism. 2002;51:906–911.

Deruelle P, Coulon C. The use of low-molecular-weight heparins in pregnancy--how safe are they? Curr Opin Obstet Gynecol. 2007 Dec;19(6):573-7.

Dhanwal DK, Dennison EM, Harvey NC, Cooper C. Epidemiology of hip fracture: Worldwide geographic variation. Indian J Orthop. 2011 Jan;45(1):15-22.

Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med. 2007 Jun 25;167(12):1240-5.

DP, Inc., Data on file.

Drake MT, Cremers SC. Bisphosphonate therapeutics in bone disease: the hard and soft data on osteoclast inhibition. Mol Interv. 2010 Jun;10(3):141-52.

Ducharme N. Male osteoporosis. Clin Geriatr Med. 2010 May;26(2):301-9.

Dwyer J. Starting down the right path: nutrition connections with chronic diseases of later life. Am J Clin Nutr. 2006 Feb;83(2):415S-20S.

Ebeling PR. Idiopathic or hypogonadal osteoporosis in men: current and future treatment options. Treat Endocrinol. 2004;3(6):381-91.

Effenberger KE, Johnsen SA, Monroe DG, et al. Regulation of osteoblastic phenotype and gene expression by hop-derived phytoestrogens. J Steroid Biochem Mol Biol. 2005 Sep;96(5):387-99.

El Maghraoui A, Ghazi M, Gassim S, Risk factors of osteoporosis in healthy Moroccan men. BMC Musculoskelet Disord. 2010 Jul 5;11:148.

Emsley, John, The Elements, 3rd edition, Clarendon Press, Oxford, 1998

Englund U, Nordstrom P, Nilsson J, et al. Physical activity in middle-aged women and hip fracture risk: the UFO study. Osteoporos Int. 2011 Feb;22(2):499-505.

Enjuanes A, Ruiz-Gaspa S, Peris P, et al. The effect of the alendronate on OPG/RANKL system in differentiated primary human osteoblasts. Endocrine. 2010 Apr;37(2):322-8.

Ewertz M, Jensen AB. Late effects of breast cancer treatment and potentials for rehabilitation. Acta Oncol. 2011 Feb;50(2):187-93.

Faloon W. Startling Findings About Vitamin D Levels in Life Extension Members. Life Extension Magazine. 2010 Jan;7-14.

Farina EK, Kiel DP, Roubenoff R, et al. Protective effects of fish intake and interactive effects of long-chain polyunsaturated fatty acid intakes on hip bone mineral density in older adults: the Framingham Osteoporosis Study. Am J Clin Nutr. 2011 Mar 2.

Fernandes G, Bhattacharya A, Rahman M, Zaman K, Banu J. Effects of n-3 fatty acids on autoimmunity and osteoporosis. Front Biosci. 2008;13:4015-20.

Ferrari S. Human genetics of osteoporosis. Best Pract Res Clin Endocrinol Metab. 2008 Oct;22(5):723-35.

Fisch C, Attia M, Dargent F, et al. Preclinical assessment of gastrooesophageal tolerance of the new antiosteoporotic drug strontium ranelate: an endoscopic study in monkeys. Basic Clin Pharmacol Toxicol. 2006 May;98(5):442-6

Fonseca JE. Rebalancing bone turnover in favour of formation with strontium ranelate: implications for bone strength. Rheumatology (Oxford). 2008 Jul;47 Suppl 4:iv17-19.

Franke S et al. Advanced glycation endproducts influence the mRNA expression of RAGE, RANKL and various osteoblastic genes in human osteoblasts. Arch Physiol Biochem. 2007 Jun;113(3):154-61.

French DL, Muir JM, Webber CE. The ovariectomized, mature rat model of postmenopausal osteoporosis: an assessment of the bone sparing effects of curcumin. Phytomedicine. 2008 Dec;15(12):1069-78.

Gabbay KH, Bohren KM, Morello R, Bertin T, Liu J, Vogel P. Ascorbate synthesis pathway: dual role of ascorbate in bone homeostasis. J Biol Chem. 2010 Jun 18;285(25):19510-20.

Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin d supplement doses and serum 25-hydroxyvitamin d in the range associated with cancer prevention. Anticancer Res. 2011 Feb;31(2):607-11.

Gennari L, Merlotti D, Martini G,et al. Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men. J Ciin Endocrinol Metab. 2003 Nov;88(11):5327-33.

Golden SH, Robinson KA, Saldanha I, Anton B, Ladenson PW. Clinical review: Prevalence and incidence of endocrine and metabolic disorders in the United States: a comprehensive review. J Clin Endocrinol Metab. 2009 Jun;94(6):1853-78.

Graham LS, Parhami F, Tintut Y, Kitchen CM, Demer LL, Effros RB. Oxidized lipids enhance RANKL production by T lymphocytes: implications for lipid-induced bone loss. Clin Immunol. 2009 Nov;133(2):265-75.

Green J, Czanner G, Reeves G, Watson J, Wise L, Beral V. Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ. 2010; 341:c4444.

Gueldner SH, Britton GR, Madhavan G, et al. Ultrasonometric profiling of incidence and risk of osteoporosis in rural women. J Women Aging. 2008;20(1-2):21-30.

Hagino H. [Epidemiology of osteoporotic fractures]. Clin Calcium. 2003;13(8):995-1002. [Article in Japanese]

Hall SL, Greendale GA. The relation of dietary vitamin C intake to bone mineral density: results from the PEPI study. Calcif Tissue Int. 1998 Sep;63(3):183-9.

Hamdy NA. Strontium ranelate improves bone microarchitecture in osteoporosis. Rheumatology (Oxford). 2009 Oct;48 Suppl 4:iv9-13.

Haney EM, Chan BK, Diem SJ, et al. Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med. 2007 Jun 25;167(12):1246-51.

Hanley DA, Cranney A, Jones G, et al. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada.CMAJ. 2010 Sep 7;182(12):E610-8.

Harkness LS, Fiedler K, Sehgal AR, Oravec D, Lerner E. Decreased bone resorption with soy isoflavone supplementation in postmenopausal women. J Womens Health (Larchmt). 2004 Nov;13(9):1000-7.

He X, Andersson G, Lindgren U, Li Y. Resveratrol prevents RANKL-induced osteoclast differentiation of murine osteoclast progenitor RAW 264.7 cells through inhibition of ROS production. Biochem Biophys Res Commun. 2010 Oct 22;401(3):356-62.

Heaney RP, Armas LA, Shary JR, 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr. 2008 Jun;87(6):1738-42.

Hein G et al. Advanced glycation end product modification of bone proteins and bone remodelling: hypothesis and preliminary immunohistochemical findings. Ann Rheum Dis. 2006 Jan;65(1):101-4.

Hein G, Weiss C, et al. Advanced glycation end product modification of bone proteins and bone remodelling: Hypothesis and preliminary immunohistochemical findings. Ann Rheum Dis. 2006 Jan;65(1):101–4.

Henriksen K, Bay-Jensen AC, Christiansen C, Karsdal MA. Oral salmon calcitonin--pharmacology in osteoporosis. Expert Opin Biol Ther. 2010 Nov;10(11):1617-29.

Hernandez JL, Olmos JM, Pariente E, et al. Metabolic syndrome and bone metabolism: the Camargo Cohort study. Menopause. 2010 Sep-Oct;17(5):955-61.

Hirao M, Hashimoto J, Ando W, Ono T, Yoshikawa H. Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K2 in postmenopausal women. J Bone Miner Metab. 2008;26(3):260-4.

Hofle G, Tautermann G, Saely CH, Drexel H. Sex-hormone-binding globulin is negatively correlated with femoral bone-mineral density in male cardiac-transplant recipients. Wien Klin Wochenschr. 2004 Mar 31;116(5-6):170-5.

Holick MF. Optimal vitamin D status for the prevention and treatment of osteoporosis. Drugs Aging. 2007;24(12):1017-29.

Holick MF. Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81.

Hoppe E, Bouvard B, Royer M, Audran M, Legrand E. Sex hormone-binding globulin in osteoporosis. Joint Bone Spine. 2010 Jul;77(4):306-12.

Horcajada-Molteni MN, Crespy V, Coxam V, Davicco MJ, Remesy C, Barlet JP. Rutin inhibits ovariectomy-induced osteopenia in rats. J Bone Miner Res. 2000 Nov;15(11):2251-8.

Howard PA, Barnes BJ, Vacek JL, Chen W, Lai SM. Impact of bisphosphonates on the risk of atrial fibrillation. Am J Cardiovasc Drugs. 2010;10(6):359-67.

Ima-Nirwana S, Suhaniza S. Effects of tocopherols and tocotrienols on body composition and bone calcium content in adrenalectomized rats replaced with dexamethasone. J Med Food. 2004 Spring;7(1):45-51.

Inoue J, Choi JM, Yoshidomi T, Yashiro T, Sato R. Quercetin enhances VDR activity, leading to stimulation of its target gene expression in Caco-2 cells. J Nutr Sci Vitaminol (Tokyo). 2010;56(5):326-30.

Isidori AM, Giannetta E, Greco EA, Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf). 2005 Sep;63(3):280-93.

Iwamoto J, Takeda T, Sato Y. Role of vitamin K2 in the treatment of postmenopausal osteoporosis. Curr Drug Saf. 2006 Jan;1(1):87-97.

Jager M, Wild A, Krauspe R. Osteonecrosis and HELLP-Syndrome. Z Geburtshilfe Neonatol. 2003 Nov-Dec;207(6):213-9.

Janssen HC, Samson MM, Verhaar HJ. Muscle strength and mobility in vitamin D-insufficient female geriatric patients: a randomized controlled trial on vitamin D and calcium supplementation. Aging Clin Exp Res. 2010 Feb;22(1):78-84.

Jeong SH, Choi SH, Kim JY, Koo JW, Kim HJ, Kim JS. Osteopenia and osteoporosis in idiopathic benign positional vertigo. Neurology. 2009 Mar 24;72(12):1069-76.

Ji G, Yang Q, Hao J, et al. Anti-inflammatory effect of genistein on non-alcoholic steatohepatitis rats induced by high fat diet and its potential mechanisms. Int Immunopharmacol. 2011 Feb 12.

Kanazawa I, Yamaguchi T, Tada Y, Yamauchi M, Yano S, Sugimoto T. Serum osteocalcin level is positively associated with insulin sensitivity and secretion in patients with type 2 diabetes. Bone. 2011 Apr 1;48(4):720-5.

Kanis JA, Johansson H, Oden A, McCloskey EV. Assessment of fracture risk. Eur J Radiol. 2009 Sep;71(3):392-7.

Kaplan JR, Manuck SB. Ovarian dysfunction, stress, and disease: a primate continuum. ILAR J. 2004;45(2):89-115.

Karabulut AB, Gul M, Karabulut E, Kiran TR, Ocak SG, Otlu O. Oxidant and antioxidant activity in rabbit livers treated with zoledronic acid. Transplant Proc. 2010 Nov;42(9):3820-2.

Katsumi H, Kusamori K, Sakane T, Yamamoto A. [Development of delivery system of bisphosphonates for the treatment of osteoporosis]. Yakugaku Zasshi. 2010 Sep;130(9):1129-33.

Katzman WB, Vittinghoff E, Ensrud K, Black DM, Kado DM. Increasing kyphosis predicts worsening mobility in older community-dwelling women: a prospective cohort study. J Am Geriatr Soc. 2011 Jan;59(1):96-100.

Kawai M, Devlin MJ, Rosen CJ. Fat targets for skeletal health. Nat Rev Rheumatol. 2009 Jul;5(7):365-72.

Kawate H, Takayanagi R. [Secondary osteoporosis UPDATE. Treatment of male osteoporosis. Testosterone replacement therapy etc]. Clin Calcium. 2010 May;20(5):744-51.

Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, et al. Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):9090-5.

Kika G, Izumi S, et al. Beneficial aspect of oral estriol as hormone replacement therapy: consideration on bone and lipid metabolism. Tokai J Exp Clin Med. 2009 Sep: 34(2): 92-98.

Kim HY, Choe JW, Kim HK, et al. Negative association between metabolic syndrome and bone mineral density in Koreans, especially in men. Calcif Tissue Int. 2010 May;86(5):350-8.

Kim MH, Bae YJ, Choi MK, Chung YS. Silicon supplementation improves the bone mineral density of calcium-deficient ovariectomized rats by reducing bone resorption. Biol Trace Elem Res. 2009 Jun;128(3):239-47.

Kim MH, Bae YJ, Choi MK, et al. Silicon supplementation improves the bone mineral density of calcium-deficient ovariectomized rats by reducing bone resorption. Biol Trace Elem Res. 2009 Jun;128(3):239-47.

Knapen MH, Schurgers LJ, Vermeer C. Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007 Jul;18(7):963-72.

Ko SS, Jordan VC. Treatment of osteoporosis and reduction in risk of invasive breast cancer in postmenopausal women with raloxifene. Expert Opin Pharmacother. 2011 Mar;12(4):657-74.

Koitaya N, Ezaki J, Nishimuta M, et al. Effect of low dose vitamin K2 (MK-4) supplementation on bio-indices in postmenopausal Japanese women. J Nutr Sci Vitaminol (Tokyo). 2009 Feb;55(1):15-21.

Kondo K. Beer and health: preventive effects of beer components on lifestyle-related diseases. Biofactors. 2004;22(1-4):303-10.

Kruger MC, Coetzer H, de Winter R, Gericke G, van Papendorp DH. Calcium, gamma-linolenic acid and eicosapentaenoic acid supplementation in senile osteoporosis. Aging (Milano). 1998 Oct;10(5):385-94.

Kupisiewicz K, Boissy P, Abdallah BM, et al. Potential of resveratrol analogues as antagonists of osteoclasts and promoters of osteoblasts. Calcif Tissue Int. 2010 Nov;87(5):437-49.

Kysenius K, Brunello CA, Huttunen HJ. Mitochondria and NMDA receptor-dependent toxicity of berberine sensitizes neurons to glutamate and rotenone injury. PloS one. 2014;9(9):e107129.

Le Merlouette M, Adamski H, Dinulescu M, et al. Strontium ranelate-induced DRESS syndrome. Ann Dermatol Venereol. 2011 Feb;138(2):124-28.

Lee HW, Suh JH, Kim HN, et al. Berberine promotes osteoblast differentiation by Runx2 activation with p38 MAPK. J Bone Miner Res. 2008 Aug;23(8):1227-37.

Lee K, Kim H, Kim JM, et al. Systemic transplantation of human adipose-derived stem cells stimulates bone repair by promoting osteoblast and osteoclast formation. J Cell Mol Med. 2011 Oct; 15(10):2082-94.

Lee YB, Lee HJ, Kim KS, et al. Evaluation of the preventive effect of isoflavone extract on bone loss in ovariectomized rats. Biosci Biotechnol Biochem. 2004 May;68(5):1040-5.

Leong KH. Osteoporosis--the need for a paradigm shift. Ann Acad Med Singapore. 1998 Jan;27(1):100-4.

Li B, Zhu WL, Chen KX. Advances in the study of berberine and its derivatives. Yao Xue Xue Bao. 2008 Aug;43(8):773-87.

Li H, Miyahara T, Tezuka Y, et al. The effect of kampo forulae on bone resorption in vitro and in vivo. II. Detailed study of berberine. Biol Pharm Bull. 1999 Apr;22(4):391-6.

Li H, Miyahara T, Tezuka Y, Tran QL, Seto H, Kadota S. Effect of berberine on bone mineral density in SAMP6 as a senile osteoporosis model. Biol Pharm Bull. 2003 Jan;26(1):110-1.

Li N, Li XM, Xu L, Sun WJ, Cheng XG, Tian W. Comparison of QCT and DXA: Osteoporosis Detection Rates in Postmenopausal Women. International journal of endocrinology. 2013;2013:895474.

Li Z, Karp H, Zerlin A, Lee TY, Carpenter C, Heber D. Absorption of silicon from artesian aquifer water and its impact on bone health in postmenopausal women: a 12 week pilot study. Nutr J. 2010;9:44.

Lieben L, Callewaert F, Bouillon R. Bone and metabolism: a complex crosstalk. Horm Res. 2009 Jan;71 Suppl 1:134-8. Epub 2009 Jan 21.

Lim JS, Kim SB, Bang HY, Cheon GJ, Lee JI. High prevalence of osteoporosis in patients with gastric adenocarcinoma following gastrectomy. World J Gastroenterol. 2007 Dec 28;13(48):6492-7.

Lips P, Bouillon R, van Schoor NM, et al. Reducing fracture risk with calcium and vitamin D. Clin Endocrinol (Oxf). 2010 Sep;73(3):277-85.

Liu ZP, Li WX, Yu B, et al. Effects of trans-resveratrol from Polygonum cuspidatum on bone loss using the ovariectomized rat model. J Med Food. 2005 Spring;8(1):14-9.

Lormeau C, Soudan B, d'Herbomez M, Pigny P, Duquesnoy B, Cortet B. Sex hormone-binding globulin, estradiol, and bone turnover markers in male osteoporosis. Bone. 2004 Jun;34(6):933-9.

Maggio M, Artoni A, Lauretani F, et al. The impact of omega-3 fatty acids on osteoporosis. Curr Pharm Des. 2009;15(36):4157-64.

Marini H, Bitto A, Altavilla D, et al. Breast safety and efficacy of genistein aglycone for postmenopausal bone loss: a follow-up study. J Clin Endocrinol Metab. 2008 Dec;93(12):4787-96.

Martin T, Gooi JH, Sims NA. Molecular mechanisms in coupling of bone formation to resorption. Crit Rev Eukaryot Gene Expr. 2009;19(1):73-88.

Matsui T, Yokoyama A, Matsushita S, et al. Effect of a comprehensive lifestyle modification program on the bone density of male heavy drinkers. Alcohol Clin Exp Res. 2010 May;34(5):869-75.

Matsushita H, Barrios JA, Shea JE, Miller SC. Dietary fish oil results in a greater bone mass and bone formation indices in aged ovariectomized rats. J Bone Miner Metab. 2008;26(3):241-7.

Maziere C, Savitsky V, Galmiche A, et al. Oxidized low density lipoprotein inhibits phosphate signaling and phosphate-induced mineralization in osteoblasts. Involvement of oxidative stress. Biochim Biophys Acta. 2010 Nov;1802(11):1013-9.

McClung M. Is altered bone health part of the metabolic syndrome? Menopause. 2010 Sep-Oct;17(5):900-1.

McFarlane SI, Muniyappa R, Shin JJ, Bahtiyar G, Sowers JR. Osteoporosis and cardiovascular disease: brittle bones and boned arteries, is there a link? Endocrine. 2004 Feb;23(1):1-10.

Mehat MZ, Shuid AN, Mohamed N, Muhammad N, Soelaiman IN. Beneficial effects of vitamin E isomer supplementation on static and dynamic bone histomorphometry parameters in normal male rats. J Bone Miner Metab. 2010 Sep;28(5):503-9.

Mehler PS, Cleary BS, Gaudiani JL. Osteoporosis in anorexia nervosa. Eat Disord. 2011 Mar;19(2):194-202.

Mettler FA, Jr., Huda W, Yoshizumi TT, Mahesh M. Effective doses in radiology and diagnostic nuclear medicine: a catalog. Radiology. Jul 2008;248(1):254-263.

Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004 Jan 29;350(5):459-68.

Miranda J. Osteoporosis drugs increase risk for serious heart arrhythmia problems. Presentation Oct. 28, 2008 at CHEST 2008.

Mikes V, Dadak V. Berberine derivatives as cationic fluorescent probes for the investigation of the energized state of mitochondria. Biochimica et biophysica acta. 1983;723(2):231-239.

Mikes V, Yaguzhinskij LS. Interaction of fluorescent berberine alkyl derivatives with respiratory chain of rat liver mitochondria. Journal of bioenergetics and biomembranes. 1985;17(1):23-32.

Mitchner NA, Harris ST. Current and emerging therapies for osteoporosis. J Fam Pract. 2009 Jul;58(7 Suppl Osteoporosis):S45-9.

Mizoguchi T, Nagasawa S, Takahashi N, Yagasaki H, Ito M. Dolomite supplementation improves bone metabolism through modulation of calcium-regulating hormone secretion in ovariectomized rats. J Bone Miner Metab. 2005;23(2):140-6.

Morabito N, Crisafulli A, Vergara C, et al. Effects of genistein and hormone-replacement therapy on bone loss in early postmenopausal women: a randomized double-blind placebo-controlled study. J Bone Miner Res. 2002 Oct;17(10):1904-12.

Morgentaler A. Turning conventional wisdom upside-down: Low Serum testosterone and high-risk prostate cancer. Cancer. 2011 Mar 1.

Morishita M, Nagashima M, Wauke K, Takahashi H, Takenouchi K. Osteoclast inhibitory effects of vitamin K2 alone or in combination with etidronate or risedronate in patients with rheumatoid arthritis: 2-year results. J Rheumatol. 2008 Mar;35(3):407-13.

Mundy GR. Osteoporosis and inflammation. Nutr Rev. 2007 Dec;65(12 Pt 2):S147-51.

Nakhla AM, Hryb DJ, Rosner W, Romas NA, Xiang Z, Kahn SM. Human sex hormone-binding globulin gene expression- multiple promoters and complex alternative splicing. BMC Mol Biol. 2009 May 5;10:37.

National Osteoporosis Foundation. CLINICIAN’S GUIDE TO PREVENTION AND TREATMENT OF OSTEOPOROSIS. Available at: http://nof.org/files/nof/public/content/resource/913/files/580.pdf. 2013.

Newton KM, LaCroix AZ, Levy L, et al. Soy protein and bone mineral density in older men and women: a randomized trial. Maturitas. 2006 Oct 20;55(3):270-7.

Nielsen FH. Studies on the relationship between boron and magnesium which possibly affects the formation and maintenance of bones. Magnes Trace Elem. 1990;9(2):61-9.

Nielsen SP, Bärenholdt O, Bärenholdt-Schiøler C, et al. Noninvasive measurement of bone strontium. J Clin Densitom. 2004;7(3):262-8.

Nielsen SP, Slosman D, Sorensen OH, et. al. Influence of strontium on bone mineral density and bone mineral content measurements by dual X-ray absorptiometry.J Clin Densitom. 1999 Winter;2(4):371-9.

Nishibe A, Morimoto S, Hirota K, et. al. [Effect of estriol and bone mineral density of lumbar vertebrae in elderly and postmenopausal women]. Nippon Ronen Igakkai Zasshi. 1996 May;33(5):353-9.

Nordin BE. The effect of calcium supplementation on bone loss in 32 controlled trials in postmenopausal women. Osteoporos Int. 2009 Dec;20(12):2135-43.

Nozaki M, Hashimoto K, Inoue Y et. al. Usefulness of estriol for the treatment of bone loss in postmenopausal women. Nippon Sanka Fujinka Gakkai Zasshi. 1996 Feb;48(2):83-8.

Nuti R, Merlotti D, Francucci CM, Gennari L. Bone fragility in men: where are we? J Endocrinol Invest. 2010;33(7 Suppl):33-8.

Ofotokun I, Weitzmann MN. HIV-1 infection and antiretroviral therapies: risk factors for osteoporosis and bone fracture. Curr Opin Endocrinol Diabetes Obes. 2010 Dec;17(6):523-9.

Oh S, Kyung TW, Choi HS. Curcumin inhibits osteoclastogenesis by decreasing receptor activator of nuclear factor-kappaB ligand (RANKL) in bone marrow stromal cells. Mol Cells. 2008 Nov 30;26(5):486-9.

Ohta H. Bazedoxifene as a new-generation SERM. Clin Calcium. 2011 Jan;21(1):34-42.

Okura T, Kurata M, Enomoto D, et al. Undercarboxylated osteocalcin is a biomarker of carotid calcification in patients with essential hypertension. Kidney Blood Press Res. 2010;33(1):66-71.

Ortolani S, Scotti A, Cherubini R. Rapid suppression of bone resorption and parathyroid hormone secretion by acute oral administration of calcium in healthy adult men. J Endocrinol Invest. 2003 Apr;26(4):353-8.

Pavese JM, Farmer RL, Bergan RC. Inhibition of cancer cell invasion and metastasis by genistein. Cancer Metastasis Rev. 2010 Sep;29(3):465-82.

Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008 Aug;8(2):157-68.

Perez-Castrillon JL, Sagredo MG, Conde R, del Pino-Montes J, de Luis D. OST risk index and calcaneus bone densitometry in osteoporosis diagnosis. J Clin Densitom. 2007 Oct-Dec;10(4):404-7.

Pfeifer M, Begerow B, Minne HW, et al. Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int. 2009 Feb;20(2):315-22.

Plosker GL, McTavish D. Intranasal salcatonin (salmon calcitonin). A review of its pharmacological properties and role in the management of postmenopausal osteoporosis. Drugs Aging. 1996 May;8(5):378-400.

Prouillet C, Maziere JC, Maziere C, Wattel A, Brazier M, Kamel S. Stimulatory effect of naturally occurring flavonols quercetin and kaempferol on alkaline phosphatase activity in MG-63 human osteoblasts through ERK and estrogen receptor pathway. Biochem Pharmacol. 2004 Apr 1;67(7):1307-13.

Przedlacki J. Strontium ranelate in post-menopausal osteoporosis. Endokrynol Pol. 2011 Jan-Feb;62(1):65-72.

Rahman MM, Bhattacharya A, Banu J, Kang JX, Fernandes G. Endogenous n-3 fatty acids protect ovariectomy induced bone loss by attenuating osteoclastogenesis. J Cell Mol Med. 2009 Aug;13(8B):1833-44.

Rahman MM, Bhattacharya A, Fernandes G. Docosahexaenoic acid is more potent inhibitor of osteoclast differentiation in RAW 264.7 cells than eicosapentaenoic acid. J Cell Physiol. 2008 Jan;214(1):201-9.

Reese AM, Farnett LE, Lyons RM, et al. Low-dose vitamin k to augment anticoagulation control. Pharmacotherapy. 2005;25(12):1746-51.

Reginster JY, Felsenberg D, Boonen S et al. Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis: Results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum. 2008 Jun;58(6):1687-95.

Reginster JY, Seeman E, De Vernejoul MC, et al. (2005). "Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: treatment of peripheral osteoporosis (TROPOS) study." J Clin Endorinol Metab 90 (5): 2816–22.

Rejnmark L, Vestergaard P, Charles P, et al. No effect of vitamin K1 intake on bone mineral density and fracture risk in perimenopausal women. Osteoporos Int. 2006;17(8):1122-32.

Rezaieyazdi Z, Falsoleiman H, Khajehdaluee M, Saghafi M, Mokhtari-Amirmajdi E. Reduced bone density in patients on long-term warfarin. Int J Rheum Dis. 2009 Jul;12(2):130-5.

Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004 Jan 29;350(5):482-92.

Roelofs AJ, Thompson K, Ebetino FH, Rogers MJ, Coxon FP. Bisphosphonates: molecular mechanisms of action and effects on bone cells, monocytes and macrophages. Curr Pharm Des. 2010;16(27):2950-60.

Rubinacci A. Expanding the functional spectrum of vitamin K in bone. Focus on: “Vitamin K promotes mineralization, osteoblast to osteocyte transition, and an anti-catabolic phenotype by y-carboxylation-dependent and -independent mechanisms”. Am J Physiol Cell Physiol December 2009 vol. 297 no. 6 C1336-C1338

Ruiz-Ramos M, Vargas LA, et al. Supplementation of ascorbic acid and alpha-tocopherol is useful to preventing bone loss linked to oxidative stress in elderly. J Nutr Health Aging. 2010 Jun;14(6):467-72.

Sacco SM, Jiang JM, Reza-Lopez S, Ma DW, Thompson LU, Ward WE. Flaxseed combined with low-dose estrogen therapy preserves bone tissue in ovariectomized rats. Menopause. 2009 May-Jun;16(3):545-54.

Salaffi F, Silveri F, Stancati A, Grassi W. Development and validation of the osteoporosis prescreening risk assessment (OPERA) tool to facilitate identification of women likely to have low bone density. Clin Rheumatol. 2005 Jun;24(3):203-11.

Salari P, Rezaie A, Larijani B, Abdollahi M. A systematic review of the impact of n-3 fatty acids in bone health and osteoporosis. Med Sci Monit. 2008 Mar;14(3):RA37-44.

Salari Sharif P, Asalforoush M, Ameri F, Larijani B, Abdollahi M. The effect of n-3 fatty acids on bone biomarkers in Iranian postmenopausal osteoporotic women: a randomized clinical trial. Age (Dordr). 2010 Jun;32(2):179-86.

Santos L, Romeu JC, Canhão H, et al. A quantitative comparison of a bone remodeling model with dual-energy X-ray absorptiometry and analysis of the inter-individual biological variability of femoral neck T-score. J Biomech. 2010 Dec;43(16):3150-5.

Sato Y, Honda Y, Kaji M, et al. Amelioration of osteoporosis by menatetrenone in elderly female Parkinson’s disease patients with vitamin D deficiency. Bone. 2002 Jul;31(1):114-8.

Scorei R, Cimpoiasu VM, Iordachescu D. In vitro evaluation of the antioxidant activity of calcium fructoborate. Biol Trace Elem Res. 2005 Nov;107(2):127-34.

Scorei RI, Rotaru P. Calcium Fructoborate-Potential Anti-inflammatory Agent. Biol Trace Elem Res. 2011 Jan 28. [Epub ahead of print]

Sedghizadeh PP, Stanley K, Caligiuri M, et al. Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: an institutional inquiry. J Am Dent Assoc. 2009 Jan;140(1):61-6.

Seeman E. The structural basis of bone fragility in men. Bone. 1999 Jul;25(1):143-7.

Sehmisch S, Erren M, Kolios L, et al. Effects of isoflavones equol and genistein on bone quality in a rat osteopenia model. Phytother Res. 2010 Jun;24 Suppl 2:S168-74.

Sehmisch S, Uffenorde J, Maehlmeyer S, et al. Evaluation of bone quality and quantity in osteoporotic mice--the effects of genistein and equol. Phytomedicine. 2010 May;17(6):424-30.

Seymour GJ, Ford PJ, Cullinan MP, Leishman S, Yamazaki K. Relationship between periodontal infections and systemic disease. Clin Microbiol Infect. 2007 Oct;13 Suppl 4:3-10.

Shakibaei M, Buhrmann C, Mobasheri A. Resveratrol-mediated SIRT-1 Interactions with p300 Modulate Receptor Activator of NF-{kappa}B Ligand (RANKL) Activation of NF-{kappa}B Signaling and Inhibit Osteoclastogenesis in Bone-derived Cells. J Biol Chem. 2011 Apr 1;286(13):11492-505.

Shiraki M, Itabashi A. Short-term menatetrenone therapy increases gamma-carboxylation of osteocalcin with a moderate increase of bone turnover in postmenopausal osteoporosis: a randomized prospective study. J Bone Miner Metab. 2009;27(3):333-40.

Shishodia S, Sethi G, Aggarwal BB. Curcumin: getting back to the roots. Ann N Y Acad Sci. 2005 Nov;1056:206-17.

Shuid AN, Mehat Z, Mohamed N, Muhammad N, Soelaiman IN. Vitamin E exhibits bone anabolic actions in normal male rats. J Bone Miner Metab. 2010 Mar;28(2):149-56.

Silverman SL. New selective estrogen receptor modulators (SERMs) in development. Curr Osteoporos Rep. 2010 Sep;8(3):151-3.

Sioka C, Fotopoulos A, Georgiou A, Xourgia X, Papadopoulos A, Kalef-Ezra JA. Age at menarche, age at menopause and duration of fertility as risk factors for osteoporosis. Climacteric. 2010 Feb;13(1):63-71.

Smith MR, McGovern FJ, Fallon MA, Schoenfeld D, Kantoff PW, Finkelstein JS. Low bone mineral density in hormone-naïve men with prostate carcinoma. Cancer. 2001 Jun 15;91(12):2238-45.

Sogabe N, Maruyama R, Baba O, Hosoi T, Goseki-Sone M. Effects of long-term vitamin K(1) (phylloquinone) or vitamin K(2) (menaquinone-4) supplementation on body composition and serum parameters in rats. Bone. 2011 Feb 2.

Sojka 1995

Song LH, Pan W, Yu YH, Quarles LD, Zhou HH, Xiao ZS. Resveratrol prevents CsA inhibition of proliferation and osteoblastic differentiation of mouse bone marrow-derived mesenchymal stem cells through an ER/NO/cGMP pathway. Toxicol In Vitro. 2006 Sep;20(6):915-22.

Spangler M, Phillips BB, Ross MB, Moores KG. Calcium supplementation in postmenopausal women to reduce the risk of osteoporotic fractures. Am J Health Syst Pharm. 2011 Feb 15;68(4):309-18.

Spector TD, Calomme MR, Anderson SH, et al. Choline-stabilized orthosilicic acid supplementation as an adjunct to calcium/vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo-controlled trial. BMC Musculoskelet Disord. 2008;Jun 11; 9:85.

Stevens JF, Page JE. Xanthohumol and related prenylflavonoids from hops and beer: to your good health! Phytochemistry. 2004 May;65(10):1317-30.

Straub DA. Calcium supplementation in clinical practice: a review of forms, doses, and indications. Nutr Clin Pract. 2007 Jun;22(3):286-96.

Sugiura M, Nakamura M, Ogawa K, et al. Dietary patterns of antioxidant vitamin and carotenoid intake associated with bone mineral density: findings from post-menopausal Japanese female subjects. Osteoporos Int. 2011 Jan;22(1):143-52.

Sun L, Tamaki H, Ishimaru T, et al. Inhibition of osteoporosis due to restricted food intake by the fish oils DHA and EPA and perilla oil in the rat. Biosci Biotechnol Biochem. 2004 Dec;68(12):2613-5.

Sveinsdóttir H, Olafsson RF. Women's attitudes to hormone replacement therapy in the aftermath of the Women's Health Initiative study. J Adv Nurs. 2006 Jun;54(5):572-84.

Takaoka S, Yamaguchi T, Yano S, et al. The Calcium-sensing Receptor (CaR) is involved in strontium ranelate-induced osteoblast differentiation and mineralization. Horm Metab Res. 2010 Aug;42(9):627-31.

Tanikawa T et al. Advanced glycation end products induce calcification of vascular smooth muscle cells through RAGE/p38 MAPK. J Vasc Res. 2009;46(6):572-80.

Tracz MJ, Sideras K, Boloña ER, et al. Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials. J Clin Endocrinol Metab. 2006 Jun;91(6):2011-6.

Trebble TM, Arden NK, Wootton SA, et al. Fish oil and antioxidants alter the composition and function of circulating mononuclear cells in Crohn disease. Am J Clin Nutr. 2004 Nov;80(5):1137-44.

Tremollieres F, Ribot C. Bone mineral density and prediction of non- osteoporotic disease. Maturitas. 2010 Apr;65(4):348-51.

Tsuang YH, Sun JS, Chen LT, Sun SC, Chen SC. Direct effects of caffeine on osteoblastic cells metabolism: the possible causal effect of caffeine on the formation of osteoporosis. J Orthop Surg Res. 2006;1:7.

Tucker KL, Morita K, Qiao N, et al. Colas, but not other carbonated beverages, are associated with low bone mineral density in older women: The Framingham Osteoporosis Study. Am J Clin Nutr. 2006 Oct;84(4):936-42.

Uesugi T, Fukui Y, Yamori Y. Beneficial effects of soybean isoflavone supplementation on bone metabolism and serum lipids in postmenopausal japanese women: a four-week study. J Am Coll Nutr. 2002 Apr;21(2):97-102.

Valcourt U et al. Non-enzymatic glycation of bone collagen modifies osteoclastic activity and differentiation. J Biol Chem. 2007 Feb 23;282(8):5691-703.

Varenna M, Gatti D. [The role of rank-ligand inhibition in the treatment of postmenopausal osteoporosis]. Reumatismo. 2010 Jul-Sep;62(3):163-71.

Vermeer C, Shearer MJ, Zittermann A, et al. Beyond deficiency: potential benefits of increased intakes of vitamin K for bone and vascular health. Eur J Nutr. 2004 Dec;43(6):325-35.

Vibert D, Kompis M, Hausler R. Benign paroxysmal positional vertigo in older women may be related to osteoporosis and osteopenia. Ann Otol Rhinol Laryngol. 2003 Oct;112(10):885-9.

Vibert D, Sans A, Kompis M, et al. Ultrastructural changes in otoconia of osteoporotic rats. Audiol Neurootol. 2008;13(5):293-301.

Volpe SL, Taper LJ, Meacham S. The relationship between boron and magnesium status and bone mineral density in the human: a review. Magnes Res. 1993 Sep;6(3):291-6.

Von Muhlen D et al. Effect of dehydroepiandrosterone supplementation on bone mineral density, bone markers, and body composition in older adults: the DAWN trial. Osteoporos Int. 2008 May;19(5):699-707. Epub 2007 Dec 15.

Wada S, Fukawa T, Kamiya S. [Osteocalcin and bone]. Clin Calcium. 2007 Nov; 17(11):1673-7.

Walker J. The role of the nurse in the management of osteoporosis. Br J Nurs. 2010 Oct 28-Nov 10;19(19):1243-7.

Ward WE, Fonseca D. Soy isoflavones and fatty acids: effects on bone tissue postovariectomy in mice. Mol Nutr Food Res. 2007 Jul;51(7):824-31.

Wattel A, Kamel S, Prouillet C, et al. Flavonoid quercetin decreases osteoclastic differentiation induced by RANKL via a mechanism involving NF kappa B and AP-1. J Cell Biochem. 2004 May 15;92(2):285-95.

Weaver CM, Martin BR, Jackson GS, et al. Antiresorptive effects of phytoestrogen supplements compared with estradiol or risedronate in postmenopausal women using (41)Ca methodology. J Clin Endocrinol Metab. 2009 Oct;94(10):3798-805.

Weiss EP, Shah K, Fontana L, et al. Dehydroepiandrosterone replacement therapy in older adults: 1- and 2-y effects on bone. Am J Clin Nutr. 2009 May;89(5):1459-67. Epub 2009 Mar 25.

Wylie CD. Setting a standard for a "silent" disease: defining osteoporosis in the 1980s and 1990s. Stud Hist Philos Biol Biomed Sci. 2010 Dec;41(4):376-85.

Xu D, Yang W, Zhou C, Liu Y, Xu B. Preventive effects of berberine on glucocorticoid-induced osteoporosis in rats. Planta Med. 2010 Nov;76(16):1809-13.

Xu P, Hu WB, Guo X, et al. [Therapeutic effect of dietary boron supplement on retinoic acid-induced osteoporosis in rats]. Nan Fang Yi Ke Da Xue Xue Bao. 2006 Dec;26(12):1785-8.

Yang MW, Wang TH, Yan PP, et al. Curcumin improves bone microarchitecture and enhances mineral density in APP/PS1 transgenic mice. Phytomedicine. 2011 Jan 15;18(2-3):205-13.

Yang YJ, Yang ZL, Wang DC, Xiao XC, Li P. [Comparative study on effects of rutin and quercetin on metabolism in osteoblast cells]. Zhong Yao Cai. 2006 May;29(5):467-70.

Yasui T, Miyatani Y, Tomita J, et al. Effect of vitamin K2 treatment on carboxylation of osteocalcin in early postmenopausal women. Gynecol Endocrinol. 2006 Aug;22(8):455-9.

Yu EW, Thomas BJ, Brown JK, Finkelstein JS. Simulated increases in body fat and errors in bone mineral density measurements by DXA and QCT. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. Jan 2012;27(1):119-124.

Zhou Z and Xiong WC. RAGE and its ligands in bone metabolism. Front Biosci (Schol Ed). 2011 Jan 1;3:768-76.

Zinnuroglu M, Dincel AS, Kosova F, Sepici V, Karatas GK. Prospective evaluation of free radicals and antioxidant activity following 6-month risedronate treatment in patients with postmenopausal osteoporosis. Rheumatol Int. 2011 Jan 8.

zur Nieden NI. Embryonic stem cells for osteo-degenerative diseases. Methods Mol Biol. 2011;690:1-30.