Building Bone: Part II: Strong Bones for Life, Naturally

Part II: Strong Bones for Life, Naturally

Bone is dynamic, living tissue that is constantly being broken down and rebuilt, even in aging adults. Although insufficient dietary calcium and the postmenopausal drop in estrogen have been singled out as the only issues, osteoporosis involves much more than simply a lack of these factors. Normal bone metabolism is an intricate interplay among more than two dozen nutrients including the vitamins D, K2, B6, B12, and folic acid, and the minerals boron, magnesium, and phosphorous as well as calcium. While estrogen regulates osteoclasts’ removal of dead portions of demineralized bone, progesterone is required by osteoblasts to build new bone mass. In addition, a variety of genetic, hormonal and lifestyle factors affect the balance between bone resorption and formation. Following is an overview of key factors affecting bone remodeling, compounds necessary for bone health, and supplement recommendations.

Calcium

Calcium is well known to be a primary component of bone, and many women, especially as they age, do not consume this essential mineral in amounts sufficient to prevent bone loss.¹ A number of studies have shown that calcium supplementation improves bone density in perimenopausal women and slows the rate of bone loss in postmenopausal women by 30 to 50%, significantly reducing the risk of hip fracture.^{2 3 4 5 6 7}

Considerations Regarding Daily Calcium Needs

The RDI for daily calcium intake in women is:

• Women 19-50: 1,000 mg
• Women 51+: 1,200 mg
• Postmenopausal women not taking HRT: 1,500 mg
• Postmenopausal women on HRT: 1,200 mg daily

Bio-identical HRT is recommended as safer than conventional patented hormones analogs.⁸ Since the Women’s Health Initiative study was abruptly halted after the early observation that conjugated equine estrogen plus progestin (medroxyprogesterone acetate) increased the risk of breast cancer, cardiovascular disease, stroke, and venous thromboembolism, patented HRT is typically recommended at the lowest possible dose for the shortest possible time for the treatment of hot flashes—which renders 33% reduction in hip fracture rate attributed to Premarin® of little use in preventing or treating osteoporosis, a condition necessitating continuous treatment to prevent excessive bone resorption.^{9 10}

The recommended dosage of supplemental calcium should factor in the patient’s dietary calcium intake, which is best estimated from analysis of a 7-10 day food diary. Regular consumption of dairy products (from cows, sheep or goats), soyfoods with added calcium, sesame seeds, and greens such as spinach, collard greens, Swiss chard, or broccoli, is likely to provide ~600 mg/day of calcium.

Choosing a Calcium Supplement

When advising patients regarding the different available forms of supplemental calcium, consider the following:

Naturally-derived calcium: may appear on labels as bone meal, oyster shell, limestone, or dolomite (clay). Since naturally derived calcium supplements have been found to contain concentrations of lead far exceeding the most recent criteria established to limit lead exposure, (> 1.5 μg/g), these forms are best avoided.^{11 12}

Calcium carbonate: the most commonly used form in calcium supplements, and that used in OTC antacids (e.g. Tums®, Rolaids®, Maalox®) is less expensive, but not as well absorbed as chelated calcium or hydroxyapaptite.

It is important that calcium carbonate be taken with meals to optimize hydrochloric acid secretion.

Calcium is absorbed in the small intestine where the pH is normal or basic; therefore, stomach acid is needed not to absorb calcium, but to dissolve the delivery form—which in the case of calcium carbonate is essentially a piece of chalk. Of concern is the fact that patients with achlorhydria absorb only about 4% of an oral dose of calcium carbonate, and studies have found that ~40% of postmenopausal women are severely deficient in stomach acid. Obviously, in patients with inadequate stomach acid production, antacids will not provide an optimal delivery form for supplemental calcium.¹³

Factors potentially contributing to insufficient stomach acid in the aging patient include Helicobacter pylori infection, gastric atrophy, and self- or prescribed medication with H2-blockers (e.g., cimetidine [Tagamet®], , ranitidine [Zantac®], famotidine [Pepcid®], and nizatidine [Axid®]) or proton-pump inhibitors for heartburn or gastroesophaegal reflux [GERD], (e.g., esomeprazole [Nexium®], omeprazole [Prilosec®], lansoprazole [Prevacid®], pantroprazole [Protonix®], rabeprazole [Aciphex®]). ^{13 14}

Chelated calcium: will appear on the label as calcium-citrate, calcium-malate, calcium-gluconate, calcium-aspartate, etc. In these chelated forms, calcium is bound to Krebs cycle intermediates, either an organic acid (e.g., citrate, malate, gluconate) or amino acid (aspartate).

Krebs cycle intermediates meet all requirements for optimal calcium-chelating agents. They are easily ionized and thus 22% to 27% better absorbed than calcium carbonate; degrade almost completely even when gastric acidity is relatively low (so can be taken without food and are the supplement of choice for achloryhydric individuals and those using H-2 blockers or protein-pump inhibitors), have virtually no heavy metal toxicity, and have been shown to increase absorption of not only calcium, but other minerals.^{2 14}

Hydroxyapatite: sometimes appears as MCHC (microcrystalline hydroxyapatite). The most expensive form of calcium, hydroxyapatite is a complex crystalline compound in which calcium is linked with phosphorus in a pre-formed building block of the bone mineral matrix. MCHC contains hydroxyapatite plus bone-derived growth factors and all the trace minerals that comprise healthy bone.

Although research on hydroxyapatite as a source of calcium is limited, two studies have shown it to be more effective in the prevention of osteoporosis due to corticosteroid therapy.^{15 16}

Always Recommend Calcium Based on Vitamin D Sufficiency:

Calcium cannot be absorbed efficiently without vitamin D. Without adequate vitamin D, the intestine absorbs ~10-15% of dietary calcium. With adequate vitamin D, the intestine absorbs 30-80% of dietary calcium (80% absorption occurs only during pregnancy and lactation).¹⁷

Vitamin D

Vitamin D Insufficiency is Pandemic in the United States

Vitamin D is essential for calcium’s absorption both from the intestines and into bone. Vitamin D deficiency—which research now shows can lead not only to osteopenia, osteoporosis, fractures and muscle weakness, but has also been implicated in depression, common cancers, autoimmune diseases including multiple sclerosis, infectious diseases and cardiovascular diseases – is the most common endocrinopathy in the U.S.¹⁷

Cherniack EP et al., (Geriatrics, April 2008) note that not only is vitamin D deficiency widespread, regardless of geographical location, but it is particularly prevalent in the elderly in whom consequences include osteoporosis, falls, increased risk of cancer, and altered glucose and lipid metabolism.

A substantial and rapidly increasing evidence base not only strongly supports the benefits of vitamin D supplementation, but also indicates that present recommendations are inadequate, especially for older individuals. Physicians should consider prescribing vitamin D3 (cholecalciferol)—at least 2,000 IU/day—to all elderly patients. Oral cholecalciferol supplementation at that level is inexpensive, safe, and effective, and has great potential to improve the quality of life of the elderly.¹⁸

Numerous Factors Impact Vitamin D Sufficiency^{13 17}

• The median adult intake of vitamin D in the U.S. is 230 IU per day.¹⁹
• The wavelength needed to produce vitamin D3 in the skin upon exposure to sunlight (UVB radiation of 290 to 320 nm) is unavailable at northern latitudes for up to 5 months of the year. Below 35° latitude, humans can produce vitamin D year round, but at higher latitudes, vitamin D production becomes increasingly seasonally limited. At ~51° latitude, we cannot make vitamin D for ~3 months. At about ~71° latitude, vitamin D production stops for more than 5 months.¹⁷
• In addition to those living in northern latitudes, individuals whose sun exposure is limited, i.e., those who are homebound; wear clothing that completely covers the body (e.g., vitamin D deficiency and rickets affect 25% of the children in Saudi Arabia because of the clothing they wear); always use sunscreen (SPF 8 reduces ability to make vitamin D by 95%); or work in occupations that prevent exposure to sunlight, are at significant risk for vitamin D deficiency.¹⁷
• Obesity is associated with vitamin D deficiency. Vitamin D is fat-soluble, so is taken into fat cells and stored. When normal and obese subjects were exposed to the same amount of UVB radiation, obese subjects produced only 55% the amount of vitamin D as normal weight subjects.^{17 20 21}
• Age affects our ability to produce vitamin D. A 70 year old has a 75% reduction in the ability to make vitamin D compared to a 20 year old due to thinner epidermis and lower concentrations of 7-dehydrocholesterol, the cell membrane constituent that UVB converts to pre-vitamin D²²; however, elders can make sufficient vitamin D if arms, legs and/or face are exposed to sunlight each day. 6,000 IU is needed daily; 6% of body surface must be exposed for 15-30 minutes to produce this. Among the homebound elderly, UV lights are very effective for vitamin D production and should be used in nursing homes.¹⁷
• Liver or kidney disorders or lack of necessary enzyme cofactors can prevent vitamin D’s conversion into its most active form. After its irradiation in the skin, 7-dehydrocholesterol is converted into vitamin D3 (cholecalciferol), transported to the liver where it undergoes conversion into 25-OHD3 (25-hydroxycholcalciferol, a compound 5 times more potent than vitamin D3, and then to the kidneys, where it is converted into 1,25-(OH)2D3 (1,25-dihydroxycholecalciferol), a compound 10 times more potent than D3. Many patients with osteoporosis have high levels of the intermediate form, 25-OHD3, and very low levels of the most active form 1,25-(OH)2D3, indicating the enzyme in their kidneys is not making the conversion. Since this enzyme is affected by estrogen, magnesium and boron, a deficiency of any of these will inhibit the conversion.¹³
• Anticonvulsants (e.g., phenobarbitone, phenytoin, and carbamazepine) interfere with vitamin D metabolism leading to hypocalcemia, low 25-hydroxyvitamin D (25(OH)D), and bone loss.²³
• Skin color is also a factor. African Americans need significantly more UV exposure to produce adequate vitamin D because the higher melanin content in darker skin reduces its ability to produce vitamin D from sunlight. Throughout the U.S., as many as 30-50% of African Americans are estimated to be vitamin D deficient.¹⁷ On the other hand, African Americans with lower 25(OH)D concentrations have higher bone mineral content (BMC), lower bone turnover rates, and different histomorphology, which results in their having one-half the osteoporosis prevalence and one-half the fracture risk of whites, despite their lower 25(OH)D concentrations.²²

Testing for Vitamin D Insufficiency17

According to leading vitamin D researcher, Michael Holick, MD, PhD, of the Boston University School of Medicine, one reason that vitamin D insufficiency is silent and misdiagnosed is that general chemical screen results can misrepresent the patient’s functional vitamin D status. If calcium is normal, it suggests the patient is vitamin D sufficient. However, this result may be misleading since when vitamin D is insufficient, intestinal calcium absorption is decreased, and ionized calcium goes down. This signals the calcium sensor in the parathyroid, which causes calcium to be shunted from the bone into circulation, so the general chemical screen will show a normal blood calcium.¹⁷

The best way to check for vitamin D sufficiency is to measure 25(OH)D3, the major circulating form of vitamin D in the blood and the true barometer of vitamin D status. Even the active hormonal form of vitamin D (1,25-(OH)2D3) does not provide adequate information since it can be normal or even elevated in a vitamin D-deficient state.¹⁷

Be sure your lab evaluates D3, as many test for D2, a plant-derived form of the vitamin that is less than half as effective as D3 in raising serum 25(OH)D, has a much shorter circulating half-life, and much weaker ability to bind to the vitamin D receptor (VDR) than D3.²⁴

Current Upper Tolerable Limit for Vitamin D Too Low

Normal range of 25(OH)D3 has been said to be 10-55 ng/ml, but this may be too low. Lifeguards typically have blood levels of 100 ng/ml (or 250 nmol/L; 1 ng = 2.5 nmol) and are not vitamin D intoxicated, so the suggested upper limit of 55 ng/ml is likely incorrect, an assumption confirmed by recent clinical trials. In one study of vitamin D3’s safety in adults with multiple sclerosis, patients’ serum 25(OH)D3 concentrations reached twice the top of the physiologic range without eliciting hypercalcemia or hypercalcuria. In this 28-week protocol, 12 patients in an active phase of multiple sclerosis were given 1,200 mg elemental calcium/day along with progressively increasing doses of vitamin D3: from from 28,000 to 280,000 IU/week. Mean serum concentrations of 25(OH)D initially were 78 +/- 35 nmol/L and rose to 386 +/- 157 nmol/L with no adverse effects.²⁵

Although, as the authors of this study note, the results suggest that vitamin D intake beyond the current upper limit is safe by a large margin, Holick thinks intoxication might occur around 150 ng/ml (375 nmol/L)—3 times the upper limit of what is considered normal. Current data support the viewpoint that the biomarker plasma 25(OH)D3 concentration must rise significantly higher—above 750 nmol/L—to produce vitamin D toxicity.²⁶ Clinically, the bottom line is that vitamin D intoxication resulting from physician-supervised supplementation is highly unlikely. Holick has found that even 5-10,000 IU vitamin D per day does not change calcium metabolism. Calcium absorption plateaus.¹⁷

The lower limit is the real, clinically relevant issue. How do you know if your patient is vitamin D-deficient? Holick’s research group’s studies suggest 25(OH)D3 should be a minimum of 20 ng/ml (45 nmol/L). Normal range is 20-100 ng/ml or even up to 150 ng/ml. Parathyroid hormone plateaus at 30-40 ng/ml, so when 25(OH)D3 is at 30 ng/ml (75 nmol/L), you’ve maximized intestinal calcium absorption in most individuals.

Blood levels of vitamin D3 sufficient to provide for bone health (as well as protecting against colon and breast cancer, multiple sclerosis, inflammatory bowel disease, depression—and a host of other ailments) begin at 30 ng/ml (75 nmol/L). Blood levels of vitamin D between ~35 to 40 ng/ml (90 and 100 nmol/L) are optimal.^{17 27 28}

Vitamin D Supplementation May be Necessary to Achieve Optimal Serum Concentrations

Sun exposure alone may not produce serum 25(OH)D concentrations indicative of optimal vitamin D status. In one recent study, only one-half of healthy and racially diverse young adult Hawaiian participants with a mean sun exposure of 29 hours/week for 3 months achieved serum 25(OH)D concentrations of 30 ng/ml (75 nmol/L). None of the participants achieved a 25(OH)D concentration of 62 ng/ml (155 nmol/L) after 3 months of 15 hours of sun exposure per week.²⁹

A daily intake = or > than1,000 IU vitamin D3 is needed to achieve these levels in at least 50% of the adult population. Those who live in northern latitudes, or live in the south but get little sun exposure or wear sunscreen, may need 2,000 IU, 5,000 IU or even up to 10,000 IU of D3 daily for 6-8 months to restore adequate levels of this critical nutrient.¹⁷ Intuitively, this is a safe dose since sunshine can provide an adult with vitamin D in an amount equivalent to daily oral consumption of 10,000 IU/day. In addition, a significant body of clinical trial evidence shows that prolonged intake of 10,000 IU/day of vitamin D3 is likely to pose no risk of adverse effects in almost all individuals in the general population, which is the criterion for a tolerable upper intake level.³⁰

To quickly restore vitamin D sufficiency, Holick recommends giving individuals with severely low vitamin D3 levels 50,000 IU once a week for 8 weeks, then 50,000 IU every other week. A 70 year old will absorb this dose as well as a 20 year old.

Ulcerative colitis patients can still absorb supplemental vitamin D since it’s absorbed in the duodenum; however, patients with diseases that affect the upper part of the small intestine, e.g., cystic fibrosis, will not be able to absorb supplemental or dietary vitamin D. For these patients, sunlight exposure is essential. In northern latitudes, use of a tanning bed, twice weekly, is recommended for 10 months, i.e., throughout the year with the exception of July and August.

Choosing a Vitamin D Supplement

Supplemental vitamin D is available in two forms, ergocalciferol (D2, a plant-derived form produced through ultraviolet irradiation of ergosterol) and cholecalciferol (D3, the form present in fatty fish and that which naturally results when the cholesterol in human skin cells is exposed to ultraviolet light). Although both are referred to as “provitamin D” since humans can convert both forms into the most active form of vitamin D, calcitriol (1,25(OH)2D3) via a two-step process initiated in the liver and completed in the kidneys, 25(OH)D3 is preferable to 25(OH)D2 since (as noted above), it is significantly more biologically active.

In humans, vitamin D3 has been found to be 2.5-fold as effective as vitamin D2 at raising and maintaining serum 25(OH)D concentrations and to have a ~40% greater ability to bind to the vitamin D receptor (VDR). ^{24 31}

Genetic Considerations

This latter consideration is especially important for individuals in whom the gene encoding the VDR exhibits one of the 22 loss-of-function mutations that have been reported. The two most studied among these are the TaqI tt and BsmI BB variants.

Individuals homozygous for the TaqI “t” allele of the VDR are much less sensitive to vitamin D, and therefore need significantly larger supplemental doses to restore and to maintain vitamin D sufficiency. Approximately 4% of African Americans and 13-18% among Asians and Caucasians carry this allelic variant, which has been found to be overrepresented among postmenopausal women with vertebral fractures (25%) compared to controls (11%), the equivalent of an odds ratio of 2.6%.³²

Incidence of the BsmI BB VDR polymorphism has also been found to be more frequent in patients with osteoporotic fractures, with one nested case control study of Caucasian-American women aged 43-69 finding a 2.4-fold greater risk of hip fracture associated with the BB compared to the Bb or bb genotypes.³³ The BsmI BB SNP is present in ~27% of Caucasians, 11% of African Americans, and 4.1% of Asians.^{34 35}

Vitamin K

In nature, vitamin K is found primarily in two forms: K1 (phylloquinone) and K2 (menaquinone): K2.³⁶ K1 is chiefly involved in blood clotting, while K2 is far more active in both bone formation and reduction of bone loss, and is also the form that has been found to protect against arterial calcification. K2 is better absorbed than K1 and remains biologically active far longer; K1 is cleared by the liver within 8 hours, while measurable levels of K2 have been detected 72 hours after ingestion.³⁷

Vitamin K is the cofactor for a single enzyme, γ-glutamylcarboxylase, which catalyzes the posttranslational conversion of glutamic acid to γ-carboxyglutamic acid (Gla) in vitamin K-dependent proteins. Carboxylation activates the Gla-proteins, which then perform a number of essential activities throughout the body, including regulating blood clotting and calcium.

K1 is preferentially utilized by the liver in the carboxylation of clotting factors, although intestinal bacteria convert a small amount into K2. K2 is preferentially used in the rest of the body to carboxylate the other vitamin K-dependent Gla-proteins, including osteocalcin (which is only able to attract calcium ions and incorporate them into hydroyxapatite crystals forming the bone matrix after carboxylation by K2), and matrix-Gla protein [MGP] (which prevents undesirable calcium deposition in soft tissue, e.g., the heart, arteries, breasts and kidneys.)

A connection has been noted between vascular calcification and osteoporosis. Patients with osteoporosis frequently suffer from vascular calcification, which has been shown to predict both cardiovascular morbidity/mortality and osteoporotic fractures. Vitamin K and D insufficiencies have been identified as common risk factors and mechanisms involved in both bone loss and vascular calcification.³⁸

Vitamin K2 Outperforms K1 Against Osteoporosis and Fracture Risk

Human studies have linked osteoporotic fracture with vitamin K insufficiency for 20+ years. Research published in 1984 found that patients who suffered osteoporotic fractures had vitamin K levels 70% lower than age-matched controls, an association that has been repeatedly confirmed. One trial involving almost 900 men and women found a 65% greater risk of hip fracture in those with the lowest blood levels of vitamin K compared to those with the highest levels of the nutrient.^{39 40 41 42 43}

In other human research, vitamin K2 has been shown to be an effective treatment against osteoporosis. A 2-year group comparison study of patients with corticosteroid-associated osteoporosis found that K2 greatly reduced vertebral fractures. Incidence of vertebral fractures was 13.3% in those taking K2 compared to 41% in the control group. In a 24-week study, 80 patients with osteoporosis were given either 90 mg/day vitamin K2 or placebo. In those taking K2, bone mineral density (BMD) increased in the second metacarpal an average of 2.2%. In those given placebo, BMD decreased an average of 7.31%.^{42 44 45}

A recent meta-analysis of randomized controlled trials in which vitamin K’s effectiveness in preventing fractures was evaluated identified 13 trials with data on bone loss, 7 of which reported fracture data. All but one study showed benefit of vitamin K (whether K1 or K2) in reducing bone loss. When data from the 7 trials with fracture analysis were pooled, K2 was significantly more protective than K1with an odds ratio favoring menaquinone (MK-4) of 0.40 for vertebral fractures, 0.23 for hip fractures, and 0.19 for all nonvertebral fractures.⁴³

A review study of all randomized controlled human trials of at least 6 months duration that assessed the use of vitamin K1 or K2 to lessen fracture risk identified 13 trials. All but one showed vitamin K reduced bone loss with K2 being significantly more effective, reducing risk of vertebral fracture by 60%, hip fracture by 77%, and all non-vertebral fractures by 81%.⁴³

Vitamin K2 Partners with Vitamin D3

Vitamin D increases production of Gla-proteins, whose activation depends on vitamin K2-mediated carboxylation. Vitamin D thus increases both the demand for vitamin K and the potential for benefit from K-dependent proteins, and the combination of K2 and vitamin D3 has been shown to be more effective in preventing bone loss than either nutrient alone. In a study of 173 osteoporotic/osteopenic women, those given both K2 and D3 experienced an average 4.92% increase in bone mineral density (BMD), while K2 alone resulted in an average BMD increase of just 0.13.⁴⁶

Concomitant use of K2 and D3 has also been found to be more effective than either nutrient alone in improving BMD in postmenopausal women. In a 2-year study, 92 postmenopausal women were assigned to one of four groups: K2 (45 mg/day), D3 (0.75 mcg/day), a combination of these dosages of K2 and D3, or calcium lactate (2 g/day). In the women receiving only calcium, lumbar BMD decreased. Those given either D3 or K2 experienced a slight increase in BMD, while those taking both K2 and D3 group fared much better, increasing lumbar BMD by 1.35%.⁴⁷

Vitamin K2 Protective Against Osteoporosis in Postmenopausal Women Not on HRT

Among postmenopausal women not using estrogen replacement, low levels of vitamin K or high levels of uncarboxylated osteocalcin are associated with low spine BMD. A 3-year study of 325 postmenopausal women, receiving either K2 (45 mg/day) or placebo, found that supplementation with K2 can prevent bone loss associated with estrogen decline. In the women given K2, bone mineral content increased, and hip and bone strength remained unchanged, whereas in the placebo group, bone mineral content and bone strength decreased significantly.⁴⁸

Choosing a K2 Supplement

Although K1 can be easily supplied via diet (best food sources include kale, spinach, Swiss chard, broccoli, Brussels sprouts, parsley and romaine lettuce), K2 is best taken in supplement form since the only excellent food source is natto, which, derived from soy, is not easily available in the U.S.and has a flavor most Americans would not find tolerable.

K2 (menaquinone) is commercially available in two forms, MK-4 and MK-7, which differ in clinically significant ways. MK-4, a short-chain menaquinone, is available as a synthetic compound (menatetrenone), while MK-7, a long chain menaquinone, is a natural menaquinone derived from natto fermentation.

Although MK-4, the synthetic form, is the one that has most often been used in the published research, after appearing quickly in the blood, it has a half-life of only 1-2 hours. For this reason, high pharmacological doses (typically 45 mg/day divided into multiple doses) are necessary. Such large doses are problematic for patient compliance and necessitate medical supervision in patients on blood-thinning medications (e.g., warfarin).

MK-7 is not only highly bioavailable and bioactive—a mere 45 mcg/day was sufficient to activate osteocalcin in the Rotterdam study—but has a much longer serum half life of 3 days, which enables the body to build up a buffer that can supply vitamin K2 to all tissues 24 hours a day. At 45 mcg/day (a dose 1,000 times less than that needed for MK-4), natto-derived MK-7 is easier for patients to use and highly unlikely to interact negatively with blood-thinning medications.^{37 49}

Boron

Boron promotes bone health via its effects on the activities of both estrogen and vitamin D in bone, and low boron intakes have repeatedly been shown to result in impaired bone health.⁵⁴

The drop in estrogen levels that occurs during menopause triggers an increase in the production of the pro-inflammatory cytokine, interleukin-6, which stimulates the production and activity of osteoclasts. An estrogen agonist, boron is necessary for estrogen’s conversion to its most potent form, 17-beta-estradiol, so boron sufficiency allows menopausal women to make the most effective use of their declining estrogen. Recent drug development is investigating a patentable form of boron as a novel SERM (selective estrogen receptor modulator) for the prevention in menopausal women reluctant to use patented HRT due to its risk of uterine cancer.⁵¹ Boron is also involved in the reaction in the kidneys in which vitamin D is converted to its most active bone-building form, (1,25-(OH)2D3), which, as noted above, is 10 times more potent than D3.2

Investigators studied the effects of boron on retinoic acid-induced osteoporosis in rats. In the osteoporotic control group, the quantity of the osteoclasts increased, and BMD decreased. In contrast, bone density, thickness and volume were significantly increased in the osteoporotic rats treated with boron, while the quantity of active osteoclasts greatly decreased. In fact, bone quality in the boron-treated rats was found to be comparable to that in the normal group.⁵²

Positive outcomes have also been demonstrated in human studies. In one study of postmenopausal women, supplementation with 3 mg/day of boron reduced urinary calcium excretion by 44% and dramatically increased levels of 17-beta-estradiol.⁵³

In another study of postmenopausal women, the increases in serum 17b-estradiol and plasma copper induced by estrogen replacement therapy (ERT) were significantly higher when boron was also consumed in the amount of 3.25 mg/day instead of 0.25 mg/day. The combination of ERT with the higher boron intake was also significantly more effective in increasing serum 25(OH)D3 concentration.⁵⁴

Best food sources of boron are apples, pears and grapes. Leafy greens, legumes and nuts can also be good sources of this mineral; however, since the boron content of fruits and vegetables depends upon that provided by the soil in which they were grown, and this can vary dramatically, boron supplementation (3.25 mg/day) is recommended.

Magnesium

Magnesium is critical for bone health. The enzyme responsible for the conversion of 25-(OH)D3 to 1,25-(OH)2D3 is dependent on adequate magnesium levels. Additionally, magnesium mediates parathyroid hormone and calcitonin secretion2, and is mitogenic for osteoblasts.⁵⁵

In one recent study of 77 postmenopausal women with osteoporosis (average age 61 years) who were age- and BMI-matched with healthy postmenopausal women as controls, the only statistically significant difference between the osteoporotic and healthy subjects was that the former had much lower red blood cell (RBC) magnesium concentrations.⁵⁵

Compared to women with healthy bones, women with osteoporosis have been found to have lower serum ionized magnesium levels, decreased RBC magnesium levels, lower bone magnesium content, lower serum concentrations of the most active form of vitamin D (1,25-(OH)2D3), and other indicators of magnesium deficiency.^{2 56 57 58 59 60 61}

Supplementation with Vitamin D May Increase Magnesium Needs

Calcium and magnesium counterbalance one another in numerous cellular activities. Patients taking vitamin D will be absorbing more calcium, and magnesium levels must be sufficient to maintain balance. Symptoms of magnesium insufficiency include migraines and tension headaches, muscle weakness, leg cramps, restless legs, elevated blood pressure, transient ischemic attacks, and arrhythmia. Particularly in patients prescribed more than 2,000 IU/day for an extended period of time, supplementation with magnesium citrate, 500 mg/bid is advised.

Strontium

More than 170 papers have been published on strontium’s bone-building effects in the last 5 years. One of the most abundant minerals on earth, strontium is chemically similar to calcium, is absorbed in comparable amounts, and once in bone, not only slows osteoclastic resorption, but enhances osteoblastic bone formation. Strontium impacts both aspects of the bone remodeling process, stimulating replication of osteoblast progenitor cells, collagen, and non-collagen protein synthesis, while also directly inhibiting osteoclast activity and differentiation.

Since pure strontium is chemically unstable, the mineral is found naturally in the form of salts, e.g., strontium sulfate, strontium chloride, strontium carbonate, strontium gluconate, strontium lactate. Strontium ranelate, a recently developed patentable salt combining strontium and the synthetic compound, ranelic acid, has been the subject of several large, double blind, placebo-controlled trials (key findings below), which have confirmed its efficacy in halting and reversing osteoporotic bone loss. The compound is currently being marketed in Europe (tradename Protelos®) for the prevention and treatment of osteoporosis.

Strontium ranelate’s efficacy in preventing early postmenopausal bone loss was evaluated in a 24-month double-blind placebo-controlled prospective randomized study of 160 postmenopausal women. All subjects received calcium (500 mg/day). Stronium ranelate (1 g/day) significantly increased lumbar BMD compared with placebo (mean [SD]: +5.53% . The annual increase for adjusted values was +0.66% compared with −0.5% for placebo, with an overall beneficial effect after 2 years of ~2.4% with strontium ranelate (1 g/day) relative to placebo. Femoral neck and total hip BMD were also significantly increased at 24 months with strontium ranelate compared to placebo (mean [SD]: +2.46% and +3.21%, respectively). Strontium ranelate was as well tolerated as placebo.⁶²

Strontium’s effects in postmenopausal women with vertebral osteoporotic fractures were also assessed in a 2-year double-blind placebo-controlled trial. Participants (353 Caucasian women) received either strontium ranelate (0.5, 1 or 2 g/day) or placebo. All patients also received a daily supplement of calcium (500 mg) and vitamin D3 (800 IU). At the study’s conclusion, the annual increase in lumbar BMD in the group receiving 2 g of strontium ranelate was +7.3%, significantly better than placebo. During the second year of treatment, the 2 gram dose was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. Treatment of postmenopausal women with established osteoporosis using strontium ranelate (2 g daily for 2 years) resulted in an increase in lumbar BMD of about 3%/year (adjusted for the presence of strontium), which was significantly higher than with placebo. The rate of increase in BMD was almost the same during the second year of treatment as during the first year. Bone histomorphometry (a method used to accurately quantify the level of cellular activity, amount of existing bone mass, and underlying cause[s]of osteoporosis) showed no mineralization defects.⁶³

The most significant of the strontium ranelate investigation to date was a large 5-year, Phase-III study, initiated in 1996, that included two clinical trials evaluating its effects on established osteoporosis: (1) the spinal osteoporosis therapeutic intervention (SOTI) study, whose aim was to assess the effect of strontium ranelate on the risk of vertebral fractures, and (2) the treatment of peripheral osteoporosis (TROPOS) trial, which evaluated the effect of strontium ranelate on non-spinal fractures. Both studies were multinational, randomized, double-blind, placebo-controlled trials with two parallel groups (strontium ranelate 2 g/day versus placebo). Primary statistical analysis was done after 3 years of follow-up. Study population included 1,649 patients (average age 70 years) in SOTI and 5,091 patients (average age 77 years) in TROPOS.

Primary (3 year) data analysis of the SOTI study, evaluating the effect of 2 g of strontium ranelate on vertebral fracture rates, revealed a 41% reduction in relative risk of experiencing a first new vertebral fracture with strontium ranelate compared to placebo. In the first year, relative risk for experiencing a new vertebral fracture was reduced 49% in the strontium ranelate group compared to placebo. Lumbar BMD increased in the treated group compared to the placebo group (+11.4% versus −1.3% respectively), and strontium ranelate was well tolerated without any specific adverse event.^{63 64 65}

Primary analysis of the TROPOS study, evaluating the effect of strontium ranelate (2 grams/day) on non-vertebral fracture, showed a reduction in risk of 16% in all vertebral fractures and a 19% reduction in risk of major non-vertebral osteoporotic fractures. In the subgroup at high risk of fracture – women aged ≥74 years and with femoral-neck BMD T score ≤−2.4 according to the National Health and Nutrition Examination Surveys (NHANES) normative value – treatment was associated with a 36% reduction in risk of hip fracture.⁶⁵

Strontium ranelate has also been studied in 1,431 postmenopausal women with osteopenia. In women with lumbar spine osteopenia, strontium ranelate decreased the risk of vertebral fracture by 41% (by 59% in women with no prevalent fractures, and by 38% in women with prevalent fractures). In women with osteopenia at both the lumbar spine and femoral neck, strontium ranelate reduced risk of fracture by 52%.⁶⁶

Most recently, strontium ranelate has been shown to reduce vertebral, non-vertebral and hip fractures in osteoporotic patients aged >74 years. Reduction of vertebral fracture risk has also been shown in osteopenic patients.⁶⁷

Safety

The safety of strontium ranelate on bone was investigated through the analysis of 141 transiliac bone biopsies performed in a subset of women enrolled in the STRATOS, SOTI or TROPOS trials. Histomorphometry provided a 2D demonstration of the bone safety of strontium ranelate, with significantly higher mineral apposition rate in cancellous bone (+9% versus control). Osteoblast surfaces were significantly higher (+38% versus control) and 3-year biopsies showed significant changes in micro-architecture, with higher cortical thickness (+18%) and trabecular number (+14%) and lower trabecular separation (−16%) with no change in cortical porosity in the strontium ranelate group. These changes in trabecular and cortical micro-architecture, which should improve bone biomechanical competence, may explain the decreased fracture rate after strontium ranelate treatment.⁶⁸

Possible ADR Concerns

Pooled data from the SOTI and TROPOS trials showed an increase in annual incidence of venous thromboembolism (0.7%) in the strontium ranelate group, and post-marketing, cases of the DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome (<20 for a total of 570,000 patient-years of exposure) have been reported in patients treated with strontium ranelate. Although strontium is a trace element naturally present in the human body, and ranelic acid is poorly absorbed, due to the possible fatality linked to this syndrome, treatment with strontium ranelate should be immediately discontinued if any suspicious major skin disorders occur within 2 months of treatment initiation.

Which leads us to question the preferential use of the new-to-nature substance—strontium ranelate—rather than the naturally occurring, but unpatentable, salt forms of this mineral by clinicians. The latter typically consist of a single strontium atom + 1 or 2 molecules of chloride, carbonate, gluconate, citrate or lactate—to which it is bound, depending on the salt. Each molecule of strontium ranelate, however, contains 2 atoms of strontium + 1 molecule of the new-to-nature compound, ranelic acid. Since strontium is the active agent in building bone, why expose patients to any increased risk of adverse events or the increased expense of a patented drug when natural forms of this agent are readily available?

Vitamin B6, Folic Acid, Vitamin B12, and Riboflavin

Each of these B vitamins plays a role in the conversion of the amino acid L-methionine to cysteine. A deficiency in any of these vitamins will cause levels of homocysteine, an intermediate metabolite in the conversion, to rise. So will the presence of a T homozygous polymorphism for the enzyme methylenetetrahydrofolate reductase (MTHFR), which is also necessary for homocysteine metabolism.

Homocysteine interferes with collagen cross-linking, causing a defective bone matrix and increased bone fragility.⁶⁹ In cultured cells, homocysteine has been shown to increase apoptosis of osteoblasts by increasing intracellular reactive oxygen species (ROS).^{70 71} High homocysteine levels are associated with increased bone turnover markers (osteocalcin and deoxypyridinoline [Dpd]) and increased hip-fracture rates independent of BMD.^{72 73}

MTHFR 677T genotype Increases Risk of Fracture

The MTHFR 677TT genotype, which is fairly common among Caucasians and Asians with a prevalence of 10-20% (>20% is seen among Italians and U.S. Hispanics, while in Blacks from Africa the rate is  = or <1% )^{74 75}, creates a 65% less-active MTHFR enzyme, leading to increased levels of homocysteine and a greatly increased risk of fracture. A 3.0 higher risk of fracture was seen in 677TT carriers in a Danish twin study.⁷⁶

Applying LeChatalier’s principle, individuals with this genotype must be given significantly higher than normal levels of vitamins B6, folic acid, B12 and riboflavin to maximize their MTHFR activity. Since a defect in MTHFR may also result in a deficiency of the activated cofactor form of folate, 5-methyltetrahydrofolate, 5-MTHFR is suggested as the preferred form of folic acid for lowering homocyteine levels.

In addition to its directly harmful effects on bone, elevated homocysteine has been linked to chronic inflammation, a significant contributing factor to bone loss in older individuals, particularly postmenopausal women not on (bio-identical) HRT.

Bone Loss and Inflammation:the RANK/RANKL/OPG System

Bone health is maintained by a balanced remodeling process that ensures continuous replacement of old bone, weakened by microfractures, with new bone. This is a tightly coupled process in which each wave of osteoclastic bone resorption is followed by one of new osteoblastic bone formation. Recently published research has revealed that the primary regulator of this coupled bone remodeling process is the RANK/RANKL/OPG system (RANK/receptor activator of NF-kappa B ligand (RANKL)/osteoprotegerin (OPG) system, explained below).

A key factor in understanding how chronic inflammation can cause this system to negatively affect bone health is the fact that osteoclasts and the cells of the immune system share a common origin in hematopoietic cells in bone marrow. Osteoclasts develop from precursors of the mononuclear monocyte-macrophage cell line after stimulation by the receptor activator of NFκB (RANK) ligand (RANKL). (Osteoblasts are of mesenchymal origin and share a common precursor cell with adipocytes.)

In bone remodeling, marrow stromal cells and osteoblasts produce RANKL, which then binds to the transmembrane receptor RANK on osteoclast precursors, inducing their differentiation and activation via the transcription factor, nuclear-factor kappa B (NFκB), which serves as the trigger not only for osteoclastogenesis, but for the body’s inflammatory response.

Both osteoclast differentiation and the inflammatory process are controlled via regulation of interleukin-6 (IL-6). A key way in which estrogen prevents excessive bone loss is by inhibiting IL-6 activation of NFκB during bone remodeling. Estrogens also decrease the responsiveness of the osteoclast progenitor cells to RANKL, thus lessening osteoclast formation. In addition, estrogens stimulate osteoblasts’ proliferation and decrease their rate of apoptosis.⁷⁷ Osteoblasts provide a further brake against excessive osteoclast formation by producing osteoprotegerin (OPG), a decoy receptor that blocks RANKL, thus also helping to maintain balance in the remodeling process.

Chronic Immune Activation/inflammation Upsets this Balance in Bone Remodeling

RANKL is also produced by activated T cells, which themselves can be induced as a consequence of an increase in oxidative stress, which translates to increased levels of reactive oxygen species (ROS).

Increased oxidative stress/ROS upregulation is associated with aging and can be greatly exacerbated by chronic, low-grade infection (as noted in Part I of this article, bisphosphonates contribute to chronic oral infections), gastrointestinal dysbiosis, a high antigenic load from food or environmental allergens, or even mild metabolic acidosis, such as is likely to result from eating the Standard American Diet. In addition to increasing oxidative stress, chronic mild acidosis increases RANK; increases osteoclastic activity; increases the activity of cathepsin K (a metallo-protease secreted by osteoclasts for bone-matrix resorption); reduces osteoblastic function; stimulates PTH secretion and prolongs its half-life, thus increasing calcium resorption; and increases urine calcium loss.²³

Increased ROS increases production of RANKL, which increases osteoclast activation.^{78 79 80} A recent review suggests the increase in oxidative stress associated with aging may be of comparable importance to the loss of estrogen that accompanies the menopause in its effects on bone health.⁸¹ This viewpoint is supported by research using ovariectomized mice (a model of menopausal estrogen loss) in which low estrogen levels did not result in bone loss without the additional presence of an increase in antigenic load, causing T-cell activation and increased ROS production.⁸²

Antioxidants Help Restore Balanced Bone Remodeling

In other research using ovariectomized mice, supplementation with N-acetylcysteine (NAC,100 mg/kg/day) and ascorbate (1 nmol/kg) was found to abolish ovariectomy-induced bone loss, adding weight to the hypothesis that the effects of estrogen deficiency on antioxidant (glutathione) levels in osteoclasts is a key contributing factor in bone hyper-resorption—and suggesting that therapies that increase oxidant defenses in bone can help prevent osteoporosis.⁸³

A randomized, double-blind, placebo-controlled pilot study has confirmed the protective effect of NAC in humans. Twenty-one early postmenopausal women (within 5 years of menopause) were randomized to receive either orally administered NAC (2 grams daily) or placebo. At 3 months, baseline C-telopeptide (a marker of bone resorption) had decreased in 80% of participants receiving NAC compared with 45% of those on placebo.⁸⁴

Alpha-lipoic acid has also been shown to abolish RANKL-induced ROS elevation and inhibit NFκB activation in osteoclast precursor cells, thus preventing osteoclastogenesis. In vitro, alpha-lipoic acid inhibited both the sustained up-regulation of RANKL expression and the production of PGE2 induced by IL-1 in osteoblasts, even in the presence of arachidonic acid, thereby inhibiting osteoclast formation and bone loss in inflammatory conditions.⁸⁵ In vivo, alpha-lipoic acid greatly suppressed bone loss induced by RANKL or TNF-alpha in mice, leading study authors to conclude “the antioxidant alpha-lipoic acid has therapeutic potential for bone erosive diseases”.⁸⁶

Ascorbic acid can also provide protection against bone loss through several mechanisms, including not only its ability to reduce oxidative stress or its role as an essential cofactor for collagen formation (bone matrix contains over 90% of protein as collagen), but also its recently discovered role in stimulating osteoblast differentiation.⁸⁷

A number of studies provide evidence that supplemental vitamin C should be considered as part of any natural protocol for bone health:

A population-based study involving 994 postmenopausal women found that vitamin C supplement users had higher BMD (3%) at the radius, femoral neck, and total hip than nonusers; women taking both supplemental vitamin C and estrogen had higher BMD at all sites; and women taking supplemental vitamin C plus calcium and estrogen had the highest BMD.⁸⁸

An earlier study reported that use of supplemental vitamin C for = or >10 years was associated with higher BMD in women (aged 55-64 years), who had not used estrogen replacement therapy compared to other nonusers in the same group.⁸⁹

A hospital based study (167 cases, 167 controls) found serum vitamin C levels were lower in cases with osteoporotic fractures than in controls. Analysis of the association between serum vitamin C and fracture risk showed a linear trend with those in the highest quartile having a significantly reduced risk of fracture (OR = 0.31).⁹⁰

A study of subjects from the prospective population-based diet and cancer study (EPIC-Norfolk) in Eastern England (aged 67-79 years at recruitment), found that women in the lowest tertile of vitamin C intake (7-57 mg/day) lost BMD at an average rate of -0.65% p.a., which was significantly faster than the loss rates seen in the middle (58-98 mg/day) and upper (99-363 mg/day) tertiles of intake, which were -0.31% p.a. and -0.30% p.a., respectively. Consumption of fruits and vegetables, whether combined or separately, showed no effect on the rate of BMD loss.⁹¹

Conclusion

Bisphosphonates stabilize bone mineral density by suppressing osteoclastic resorption, which, when not excessive, is essential for bone health. Over-suppression of the osteoclastic arm of bone remodeling leads to increased accumulation of microdamage, impaired mineralization, increased brittleness, and increased risk, not only of ONJ, but fracture. When the balance between osteoclastic demolition and osteoblastic reconstruction can be restored by addressing the causes of excessive osteoclast activity and providing an adequate supply of the materials necessary to build new bone, bisphosphonates are not the best option for first-line therapy.

An awareness of the intricate interplay among the nutrients key to bone health, and the impact of genetic, hormonal and lifestyle factors on the balance between bone resorption and formation enables the informed clinician to develop an effective protocol that avoids bisphosphonate-associated risks, targets the individual patient’s needs and supports healthy bone remodeling throughout life.

Read Part I: Building Bone: Natural Alternatives Offer Better Options to Bisphosphonates—The Case Against Bisphosphonates

References