The Journal for Nurse Practitioners
Volume 6, Issue 3 , Pages 193-198, March 2010

Complementary Therapies in Osteoporosis

  • Darlene Higgs

      Affiliations

    • Darlene Higgs, RN, BSN, is an NP student at the University of Tampa in Tampa, FL.
    • ,
  • Cathy Kessenich

      Affiliations

    • Cathy Kessenich, DSN, ARNP, is a professor of nursing at the University of Tampa in Florida.

Article Outline

Abstract 

Osteoporosis is a disorder characterized by brittle, fragile bones. It results from unbalanced bone metabolism and often leads to bone fractures and, consequently, a decreased quality of life. It is complex in pathology and requires multifactorial management and treatment. It is imperative that nurse practitioners (NPs) maintain current best-practice knowledge to appropriately manage and treat this increasingly prevalent and debilitating disease. This article provides a review of information regarding recent evidence for pharmacological and supplemental therapies in osteoporosis, including strontium ranelate, genistein, and vitamin K.

Keywords:  genistein , osteoporosis , strontium , vitamin K

 

Osteoporosis is a disorder of unbalanced bone remodeling. It occurs when bone resorption exceeds bone formation, resulting in porous bones and ultimately a decrease in bone density and strength. Patients with osteoporosis are at great risk for bone fractures, which lead to health care expenditures and a decreased quality of life.

Osteoporotic fractures can occur in any part of the skeleton, but most commonly affect bones of the hip, spine, and wrist. Osteoporosis is influenced by genetics, age, sex, race, lifestyle factors, and dietary intake. It is complex in pathology and therefore requires multifactorial management and treatment.

Approximately 10 million Americans over 50 years of age suffer from osteoporosis and an additional 34 million are at risk due to low bone mass. Of those over 50 with osteoporosis, approximately half of the women and a quarter of the men will experience an osteoporosis-related fracture within their lifetime. Ensuing fractures cost Americans an average of $19 billion each year and are the cause of 180,000 yearly nursing home admissions.1 These numbers are expected to rise in conjunction with the mounting elderly population and increasing life expectancy.

It is important for nurse practitioners (NPs) to be aware of advances in treatment options for osteoporosis. Every patient is unique and may require treatment alternatives due to allergic reactions, side effects, or personal preference. NPs should be aware of current evidence-based knowledge concerning various treatment options to make them available to patients. Traditional osteoporotic therapy includes pharmacological interventions as well as nutrient supplementation. Current pharmacological treatments include oral and intravenous bisphosphonates, selective estrogen receptor modulators (SERMs), calcitonin, and parathyroid hormone (PTH) injections, while calcium and vitamin D are supplemental cornerstones for the prevention and treatment of osteoporosis. This article addresses recent evidence suggesting that strontium ranelate (SR) may be a beneficial pharmacological therapy and also explores the evidence regarding supplementation with the soy isoflavone genistein and Vitamin K.

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Strontium Ranelate 

Stable strontium, along with calcium and magnesium, is a naturally occurring metal found in the body. It is not to be confused with the radioactive forms of this element. Greater than 99% of the body's strontium content is found in bone. There are various forms of stable strontium, including strontium ranilate, strontium citrate, and strontium carbonate. In vitro and in vivo studies have found that stable strontium increases bone formation and decreases bone resorption.2

Strontium ranelate (SR) is the most extensively studied form of stable strontium and is a relatively new osteoporotic therapy available in Australia and Europe. Unlike other osteoporotic drugs, SR maintains bone structure by dual mechanism. It both stimulates osteoblasts and inhibits osteoclasts, thereby simultaneously increasing bone formation and reducing bone resorption.3 Data pooled by the Cochrane Collaboration review determined that SR decreases vertebral and nonvertebral fracture risk by 37% and 14%, respectively.4 SR appears to effectively reduce vertebral fractures in postmenopausal women but the drug has not yet been approved for use in the United States5 and is currently under consideration for approval in Canada.6

SR is composed of 2 stable strontium atoms combined with the carrier ranelic acid. While trials have identified various aspects of the SR mechanism, the exact pathway remains unclear. In vitro trials suggest that the primary mechanism of SR may be the activation of calcium-sensing receptors (CaR) through its anatomic and ionic similarities to calcium. CaR activation is involved in osteoblast differentiation and osteoclast apoptosis, thus addressing both bone formation and resorption.3

The most well-known SR studies are the SOTI (Spinal Osteoporosis Therapeutic Intervention) trial and the TROPOS (Treatment of Peripheral Osteoporosis) trial. These large-scale, phase 3, randomized, double-blind, clinical-controlled trials were conducted to determine the effect of 2 grams of oral SR daily on vertebral and nonvertebral fractures. The SOTI trial analyzed vertebral fracture risk and the TROPOS study analyzed nonvertebral fracture risk. Both trials were conducted simultaneously in 12 different countries and 75 different treatment centers.7

After the 3-year SOTI study, the risk reduction for vertebral fractures was 41%, and the bone mineral density (BMD) increased from baseline by 14.4% at the lumbar spine, 7.2% at the femoral neck, and 8.6% at the total hip.8 The 3-year TROPOS trial determined that SR reduced the relative risk for nonvertebral fractures by 16%.9 For those women considered at high risk for fracture (≥ 74 years with a BMD of ≤ −3 at the femoral neck), the relative risk for incurring a hip fracture was reduced by 36%. Femoral-neck BMD increased by 8.2% and total-hip-BMD by 9.8%. The TROPOS 5-year follow-up reports a nonvertebral fracture risk reduction of 15%, and a 43% reduction in the risk for hip fractures.10 While SR appears effective, it is important to recognize that the SOTI and TROPOS trials were supported by Servier, the manufacturer of strontium ranelate.

The main adverse effects of SR are nausea and diarrhea,11 with trials showing no increased risk of serious adverse events in the treatment groups.4 After 5-year trials, SR appears to have a high safety profile.10 Practitioners should be aware that adverse cases of DRESS (drug rash with eosinophilia and systemic symptoms) have been reported since the marketing of SR and, although it is very rare, it is important to recognize, as the syndrome may be fatal. In the case of DRESS, SR therapy should be promptly and permanently discontinued. DRESS usually resolves with termination of therapy.11

SR is marketed as Protelos in countries in which it is approved. Protelos is in powder form, containing 2 grams of strontium ranilate and is given orally by suspension in a liquid.12 Strontium is also available to the public in supplemental forms as strontium citrate and strontium carbonate. Strontium citrate can be found in dosages of 340 mg to 1000 mg and strontium carbonate is present in various over-the-counter osteoporosis complexes. However, the recommended daily allowance (RDA) for these strontium forms has not been determined and its efficacy has not been proven.

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Genistein 

The bone-building effects of soy isoflavones have been explored over the past decade. Genistein is a soy isoflavone that has recently gained attention for its apparent benefit as an osteoporotic therapy for postmenopausal women. Isoflavones are found in soy-rich foods such as soy beans, tofu, and miso. These are staple foods in Asian populations, where they are consumed at 10 to 20 times the rate of Western populations. This may contribute to the significantly lower rate of osteoporosis seen in Asian women as compared to American women.13 Animal trials have shown that genistein increases bone mass14 and prevents bone loss.15 Human clinical trials have shown both a decrease in bone resorption markers and an increase in bone formation markers,16, 17, 18 along with an increase in BMD.17, 18

Genistein appears to facilitate bone changes through its phytoestrogenic properties. This plant-derived estrogen is molecularly similar to the endogenous estrogen 17-β estradiol.19 During the peri- and postmenopausal period, estrogen decline causes bone resorption to accelerate. Estrogen replacement therapy (ET) was once commonly prescribed therapy for peri- and post-menopausal women. However, this has changed due to evidence of the detrimental effects that ET may have on breast and uterine tissue in women, including increased risk of breast, endometrial, and ovarian cancer, and cardiovascular events, such as heart disease, venous thromboembolism, and stroke.17 Genistein may be a safe, naturally occurring alternative to ET for the prevention and treatment of osteoporosis. Trials indicate that genistein has a positive effect on bone remodeling without affecting reproductive tissues.16, 18

Unlike pharmaceutical estrogen therapy, genistein is hormone-receptor specific. It has a profuse affinity for estrogen receptors in the bone, with less attraction to receptors in the breast and endometrial tissue. There are 2 primary estrogen receptors found in the body, ER-α and ER-β. ER-α is found primarily in the reproductive tissues, while bone contains large amounts of ER-β. Genistein's affinity for ER-β is approximately 7 times greater than its affinity for ER-α.20 Genistein appears to replace estrogen and reduce bone resorption without affecting reproductive tissues.16, 18 Soy isoflavones may also positively affect cardiovasculature, reducing cholesterol and decreasing cardiovascular disease.21 Trials involving various isoflavones (including both food and pill forms of soy isoflavones) have shown increased BMD at the spine13, 22 and Wards triangle.22 Possibly the most noteworthy study on soy isoflavones and bone is the recently conducted, randomized, double-blind, placebo-controlled trial by Marini et al,17, 18 in which the isoflavone genistein was used. The trial involved postmenopausal women with femoral neck BMD below 0.795 g/cm2. Supplementation of 54 of mg pure genistein daily for 2 years resulted in a significantly greater BMD in the lumbar spine and femoral neck for the intervention group. Meanwhile, BMD decreased in the control group. Genistein also increased markers of bone formation and decreased markers of bone resorption. Marini et al18 continued to see positive effects on bone mineralization markers and increased BMD during their 3-year follow-up study, conducted to determine the safety of genistein. The authors also determined that after 3 years of treatment with 54 mg of genistein aglycone, there were no significant changes in breast density or endometrial thickness.

Genistein may be a safe, effective, and natural alternative to ET for the treatment of osteoporosis in postmenopausal women. It is a bone-receptor-selective phytoestrogen with the efficacy of ET.16 Clinical trials have shown that it increases BMD by both enhancing bone formation and reducing bone resorption.16, 17, 18 The soy foods most abundant in isoflavones, including genistein, are: whole soybeans, roasted soy beans, soy flour, tempeh, tofu, miso, and certain protein isolates.21 Genistein can also be found in supplemental forms. Dosages of 54 to 90 mg of genistein daily appear to be effective at enhancing bone remodeling.13, 16, 17

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Vitamin K 

Vitamin K is a vital element in numerous bone-forming mechanisms of the body. Vitamin K has been shown to moderately increase BMD but, more importantly, it prevents fractures in postmenopausal osteoporotic populations. Unlike other osteoporotic treatments, the antifracture efficacy of vitamin K relies primarily on enhanced bone quality rather than increased bone mass.23 Bone quality encompasses bone turnover, architecture, and matrix.23

There are 2 naturally occurring forms of vitamin K: vitamin K1 (phylloquinone) and vitamin K2 (menaquinone). K1 is the dietary form of vitamin K found in green leafy vegetables. K2 is found in animal sources, such as fermented dairy and soy products, fish, meat, liver, and eggs, and is also synthesized by intestinal bacteria.24

While both forms of vitamin K have positive effects on bones, K2 is more potent and effective than K1.25 K2 reduces fractures26 and moderately increases BMD,26, 27 and has been used in Japan as a treatment for osteoporosis for more than a decade.25 Vitamin K may have been overlooked as a treatment option for osteoporosis in the United States because of its modest effect on BMD. However, the bone-enhancing effects of vitamin K become more apparent upon analyzing fractures. The fracture reduction seen in clinical trials is likely due to improved bone quality, rather than increased bone mass.

Vitamin K improves bone quality by enhancing the architectural structure of bone and collagen. While the details of the mechanism are uncertain, carboxylation of osteocalcin appears to be its major means of enhancing bone strength.23 High levels of undercarboxylated osteocalcin have been linked with low bone density28 and a higher risk of hip fracture.29 Clinical trials show that vitamin K increases carboxylation of osteocalcin.25 The average American may not ingest enough vitamin K to support carboxylation of osteocalcin.30

Epidemiologic studies have shown that a high intake of vitamin K correlates with reduced fracture risk.31, 32 The Nurses' Health study determined that women who ate lettuce each day had a 45% lower risk of developing a hip fracture than those women who ate lettuce on a weekly basis or less often.32 The Framingham Heart study followed with similar results, finding that participants in the highest vitamin K intake quartile had an adjusted fracture risk reduction of 65% compared to those in the lowest intake quartile.25, 31

Clinical trials also support that vitamin K reduces fractures and elicits positive effects on BMD, particularly with menaquinone supplementation. A recent meta-analysis concluded with a hip fracture reduction of approximately 80% among the reviewed trials of vitamin K supplementation. However, the authors caution that there may be an unidentified reason for such a high reduction in hip fractures, stating that many of the trials included were not high-quality and some had high attrition rates. Most occurred in Japan, which may suggest the findings are not generalizable to other areas.26

Two, randomized, double-blind, placebo-controlled trials have been conducted to determine the effect of vitamin K on bone. One trial supplemented with K227 and the other K1.33 Until these recent trials, vitamin K research lacked this gold standard of support.

When comparing K2 supplementation to placebo, Purwosunu et al27 reports a significant increase in BMD and a significant decrease in uncarboxylated osteocalcin. The trial was conducted in Indonesia, involving 63 postmenopausal women with osteoporosis. The intervention group (n = 33) was given 45 mg of K2 with 1500 mg of calcium carbonate, and the control group was given a placebo with 1500 mg of calcium carbonate daily for 48 weeks. When compared to baseline, BMD increased by 1.74 ± 0.43% in the intervention group and decreased by 0.18 ± 0.24% in the placebo group. Uncarboxylated osteocalcin decreased from baseline by 55.9% in the intervention group and 9.3% in the control group, with a significant difference between the 2 groups.27 As previously mentioned, uncarboxylated osteocalcin has been linked with increased fracture risk.29 Unfortunately, this K2 trial does not report fractures that occurred during the study.

Cheung et al33 conducted a trial over a 4-year period using K1 supplementation. No significant difference was found in BMD between the intervention and control groups but there were fewer fractures in the intervention group. Four hundred forty postmenopausal women with osteopenia were enrolled in the trial; the intervention group was given 5 mg of K2 daily and the control group was given a placebo. BMD decreased in both the intervention group and the control group (−1.28% and −1.22%, respectively, P = 0.84); however, there were only 9 fractures in the intervention group and 20 fractures in the control group.33

Current data suggest that vitamin K increases bone strength and reduces fractures in postmenopausal patients with low bone density.26, 27, 33 While both forms of vitamin K show positive effects, K2 is the more effective of the two, and therefore the first choice for supplementation. K2 supplementation has also shown synergistic effects on bone when combined with vitamin D334, 35 and when given in conjunction with bisphosphonates.36 K2 may also be a beneficial adjunct during treatment with drugs such as leuprolide and prednisone, as clinical trials have shown that it counteracts the bone-depleting effects of these drugs.36

Daily adequate intake (AI) recommendations for K1 are 90 μg for women and 120 μg for men.24 There is currently no established recommended daily intake of K2. With regard to osteoporosis treatment, daily doses of 1000 μg of K1 and 45 mg of K2 have been suggested according to research outcomes.25 A safe upper limit of vitamin K has not been established due to a lack of adverse effects. The studies reviewed here showed no evidence of toxicity at these levels and the only reported adverse effects were mild gastrointestinal complaints. The reference range for plasma vitamin K is 1.3 to 1.9 ng/mL.37 Serum K2 levels below 1.10 ± 0.07 ng/mL and K1 levels below 0.64 ± 0.06 ng/mL have been linked with a lower than normal BMD in postmenopausal women.37

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Conclusions 

Strontium ranelate can provide osteoporotic patients with both increased bone formation and decreased bone resorption. While SR is not yet available for prescription in the United States, it is important for practitioners to understand the mechanism and efficacy of the drug, as they may encounter patients from outside the country who are taking this prescriptive therapy. It is also essential to note that women with osteoporosis may take strontium citrate or strontium carbonate as a supplemental therapy. Patients taking these supplements should be advised that their safety and efficacy have not been clinically proven.

Genistein is a receptor-selective phytoestrogen with the efficacy of estrogen therapy16 but without the detrimental effects on reproductive tissues.18 It increases BMD and reduces bone resorption.16, 17, 18 Daily intake of genistein may effectively prevent and treat osteoporosis in postmenopausal populations. Genistein can be ingested through supplements or dietary intake of soy products. Many patients prefer herbal and supplemental therapies in treating disease. Genistein may be a safe, effective, supplemental treatment option for these populations.

K2 appears to safely and effectively increase BMD and reduce fractures. There is no evidence of vitamin K toxicity, and side effects relate only to mild gastrointestinal effects.25, 26 A daily dose of K2 may be considered as a supplemental therapy for postmenopausal osteopenia and osteoporosis to reduce fractures.

Many Americans prefer supplemental and complementary therapies over prescription agents. It is important to be open and accepting of patients' choices and it is equally as important to be knowledgeable and honest concerning available therapies. A well-rounded treatment regimen for osteoporotic patients includes lifestyle modifications and both pharmacological and supplemental medication. Treatment of osteoporosis should begin with appropriate lifestyle modifications such as a balanced diet with nutritional supplementation if necessary, regular exercise, and fall-prevention strategies. Adjunct pharmacologic and supplemental therapies should be patient-specific, dependent upon degree of osteoporosis and concomitant clinical conditions. NPs should maintain current knowledge regarding available evidence-based treatments for osteoporosis, both supplemental and pharmacologic, to provide the safest and most effective options for their patients.

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References 

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Uncited reference 

  1. Kanai T , Takagi T , Masuhiro K , Nakamura M , Iwata M , Saji F . Serum vitamin K level and bone mineral density in post-menopausal women . Int J Gynecol Obstet . 1997;56:25–30

 In compliance with national ethical guidelines, the authors report no relationships with business or industry that would pose a conflict of interest.

PII: S1555-4155(09)00588-1

doi:10.1016/j.nurpra.2009.10.003

The Journal for Nurse Practitioners
Volume 6, Issue 3 , Pages 193-198, March 2010

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