Osteoporosis: Beyond Bone Mineral Density (Part II)John Neustadt, ND, and Steve Pieczenik, MD, PhD Primary osteoporosis occurs with bone loss as people age, and life-shortening fractures in patients. Early detection and while secondary osteoporosis is caused by other factors such as treatment of risk factors for osteoporosis and osteoporotic frac-medications and medical conditions. Debilitating acute and tures are essential for practicing clinicians.
chronic pain in the elderly is often attributed to fractures from Family physicians will frequently be the doctors who recom- osteoporosis and can lead to further disability and early mortal- mend screening for osteoporosis and who are uniquely posi- ity. Osteoporosis is generally viewed as a disease of low bone tioned to ensure both detection and appropriate treatment. mineral density (BMD) as defined by a T-score. However, Understanding bone histology, the physiology of bone turnover, T-scores and, hence, BMD criteria may not accurately reflect and current research on the prevention and treatment of osteo-fracture risk. Thus, if clinicians are too reliant on the idea that porotic fractures including pharmaceutical and nutritional inter-BMD/T-scores are the major concern in fracture risk, they may ventions can contribute towards the development of an integra-fail to recognize other danger signs and prevent painful, costly, tive approach to treating this condition.
Editor's note: This is the second of a 2-part article. Part 1 was 5-year period was published in the Journal of Orthopaedic published in the Oct/Nov 2008 issue of IMCJ (IMCJ 7.5:34-38). Trauma.58 During that time period, 70 patients (59 women, 11 men; mean age 74.7 years) were evaluated. Twenty-five of these patients had been taking alendronate, and, of those 25, there After reading Part I of this article, you are now aware of the were 19 (76%) who experienced a "transverse fracture with a complex issues surrounding osteoporosis and the risk fac- unicortical break in an area of cortical hypertrophy." In contrast, tors for osteoporotic fractures. In this second article, we only 1 patient (2%) not being treated with alendronate suffered will discuss pharmacological and nutritional therapies for treating this fracture pattern. The odds ratio of a fracture for people tak- the disease.
ing alendronate was 139.33 (P<.0001). The average duration of alendronate treatment was significantly greater in those with the Integrative Approaches for Prescriptions fracture pattern compared to those without this pattern: 6.9 years versus 2.5 years, respectively (P=.002). Once the need for intervention has been decided, what At least 2 additional retrospective analyses have come to should a physician recommend? similar conclusions. One study published in The Journal of Bone and Joint Surgery identified 13 women who suffered subtrochan- teric fractures with minimal or no trauma over a 10-month Pharmacological therapy is the standard of care for conven- period from May 2005 to February 2006 in 2 hospitals in tional approaches to osteoporosis treatment. Antiresorptive Singapore.59 Of those women, 9 had been taking alendronate for pharmacological medications, such as alendronate (Fosamax), an average of 4.2 years (2.5 to 5.0 years; mean age 66.9 years), risedronate (Actonel), raloxifene (Evista), and parathyroid hor- and 4 had not been taking alendronate. Interestingly, of these mone minimally improve bone mineral density (BMD). They 13, 4 reported a BMD score that put them in the category of also have been shown to effectively decrease vertebral fracture osteopenia rather than osteoporosis. Three others reported risk by 47% for alendronate,50 49% for risendronate,51 30% for BMD scores that placed them in the osteoporosis category, and raloxifene,52 and 65% for parathyroid hormone53 (see Table 5 in the rest did not report a score.
the conclusion of this article). However, some studies have con- Another report of US cases is particularly condemning: The cluded that, with antiresorptive drug therapies, BMD accounts report identified 9 patients who experienced traumatic nonspi- for only 4% to 28% of the reduction in vertebral fracture risk.54-57 nal fractures after 3 to 8 years of alendronate therapy "while Thus, focusing solely on therapies that increase BMD does not performing normal daily activities such as walking, standing, or maximize potential clinical benefits.
turning around."60 These patients continued taking alendronate Additionally, new evidence is suggesting that treatment after their fracture, and 6 of those patients exhibited delayed with bisphosphonate medications may actually increase fracture fracture healing for 3 months to 2 years after the fracture. risk after approximately 7 years of use. A recent retrospective While preliminary, these reports are alarming. There is evi- review of patients admitted to a Level 1 trauma center over a dence that alendronate therapy may suppress bone remodeling Integrative Medicine • Vol. 7, No. 6 • Dec 2008/Jan 2009
Neustadt and Pieczenik—Osteoporosis to the point of increasing fracture risk in some patients. This risk Clinicians should understand that there are primarily 2 may be extremely small, but no long-term prospective study has forms of vitamin K , MK4 and MK7, commercially available. been carried out to quantify this risk. In the meantime, clinicians MK4 is a synthetic form of vitamin K and the agent used in the may consider other medication and/or a more integrative clinical trials mentioned below. MK7 is produced by bacterial approach than monotherapy with alendronate to help decrease fermentation of soy, appears to have a longer half life then MK4, fracture risk in their patients. and can also decrease serum undercarboxylated osteocalcin (ucOC).66 However, only MK4 has demonstrated the ability to decrease fracture risk, the clinically relevant end point in ran- One of the conceptual problems with many clinical trials of domized, controlled clinical trials on bone health.
dietary supplements for BMD or fracture prevention is that they Taking broad-spectrum antibiotics can reduce vitamin K tend to study effects of only 1 or maybe 2 added nutrients. production in the gut by nearly 74% in people compared to those However, bone is a complex mixture of different minerals, and not taking these antibiotics.67 Diets low in vitamin K also even minerals that are not found in the bone matrix are still decrease the body's vitamin K concentration.68 Additionally, in required as cofactors in bone remodeling. The importance of the elderly, there is a reduction in vitamin K production.69 vitamin and mineral supplements in maintaining bone health Natto (fermented soybean) is the richest dietary source of vita- was demonstrated in a study of postmenopausal women ages 50 min K . Dairy products (milk, butter, cottage cheese, cheese) and to 60.61 Those women who took a complex supplement contain- egg yolk also provide small amounts. ing calcium, magnesium, zinc, and vitamins D and K lost signifi- It's important to note that vitamin K is preferentially used cantly less BMD than those who did not take the supplement. by the liver as a clotting factor. Vitamin K on the other hand is used preferentially in other organs, such as the brain, vascula- Calcium and Vitamin D
ture, breasts, and kidneys. Coagulation studies in humans using Calcium and vitamin D are currently recommended for the 45 mg per day of vitamin K (as MK4)70 and even up to 135 mg/ primary prevention of osteoporosis and the primary and second- day (45 mg tid) of K (as MK4),71 showed no significant increase ary prevention of osteoporotic fractures. in pathologic coagulation risk. In fact, doses in rats as high as Secondary prevention of osteoporotic fracture was assessed in 250 mg/kg body weight did not alter the tendency for blood clot a trial of 5292 people aged 70 years or older (mean age, 77 years).62 formation to occur.72 Volunteers (85% female) were randomized to receive 1 of 4 proto- Vitamin K exerts a powerful influence on bone building, cols: 800 IU vitamin D , 1000 mg calcium carbonate, 800 IU vita- especially in osteoporosis, and in Japan has been accepted as an min D plus 1000 mg calcium carbonate, or placebo daily for up to osteoporosis treatment.73 It is a fat-soluble vitamin that is a 62 months (median duration, 45 months). In this trial no signifi- coenzyme for a vitamin K-dependent carboxylase enzyme that cant difference in fracture risk was detected among the groups. catalyzes carboxylation of the amino acid glutamic acid, result- However, another study noted a 16% reduction in fracture ing in its conversion to gamma-carboxyglutamic acid (Gla). This risk (P<.025) over 3 years in 2532 community-dwelling residents carboxylation reaction is essential for formation of bone colla- (median age, 73 years; 59.8% female) who supplemented with gen, which allows bone to deform upon impact, for example 400 IU vitamin D and 1000 mg calcium as calcium carbonate during a fall, without fracturing. Although vitamin K-dependent daily.63 As well, in a randomized, open-label, 2-year sequential gamma-carboxylation occurs only on specific glutamic acid resi- follow-up study of 43 healthy adult volunteers (14 men, mean dues in a small number of proteins, it is critical to the calcium- age 60.6 years; 29 postmenopausal women, mean age 54.1 binding function of those proteins. years), participants followed their usual diet for the first year and Three vitamin K-dependent proteins have been isolated in then were randomized to receive 500 IU vitamin D and 500 mg bone—osteocalcin, matrix Gla protein, and protein S. Of these, calcium (form of calcium not reported), or no supplementation, osteocalcin is a protein that is synthesized by osteoblasts and from October to March.64 During these winter months in which regulated by the active form of vitamin D, 1,25-(OH) D , also volunteers took vitamin D and calcium, their lumbar BMD was called calcitriol. The mineral-binding capacity of osteocalcin 0.8% greater than in controls (P=.04), while no significant differ- requires vitamin K-dependent gamma-carboxylation of 3 glu- ences between the groups were noted for femoral-neck BMD.
tamic acid residues. Multiple randomized, double-blind, place-bo-controlled clinical trials have shown significant decreases in ucOC in volunteers supplemented with 45 mg of vitamin K with Vitamin K is a group of structurally similar, lipid-soluble, and without the addition of calcium and vitamin D compared 2-methyl-1,4-napthoquinones, which include phylloquinone to controls.69,74-76 (K ), menaquinones (K ), and menadione (K ).65 Plants synthe- A 2006 meta-analysis published in the Archives of Internal size vitamin K while bacteria can produce a range of vitamin K Medicine by Sarah Cockayne, MSc; Joy Adams, forms, including the conversion of K to K by bacteria in the PhD; and colleagues, at the University of York in small intestines. Vitamin K is synthetic and, because of its toxic- England, evaluated clinical trials on vitamin K and fracture ity, has been banned in by the US Food and Drug Administration risk.77 They identified 13 randomized, controlled trials of the for human uses. In contrast to vitamin K , no known toxicity effect of vitamin K on osteoporosis. Of those, 7 had fracture risk exists for the vitamin K and K forms. as an end point and so were included in their meta-analysis. Neustadt and Pieczenik—Osteoporosis Integrative Medicine • Vol. 7, No. 6 • Dec 2008/Jan 2009
They concluded that 45 mg of vitamin K as menaquinone-4 trations of vitamin D.84 Additionally, people with low BMD have (MK-4) could decrease vertebral fracture by 60%, hip fracture by lower zinc concentrations in their bones.87 Copper and zinc are 73%, and all nonvertebral fractures by 81%.
important for bone health. Zinc is found in the bone matrix An excellent review of vitamin K by Stephen Plaza, incorporated into hydroxyapatite crystal. It is also involved in and Davis Lamson, ND, was published in 2005 in the journal stimulating osteoblastic activity while suppressing osteoclastic Alternative Medicine Review.65 In this article they reviewed clini- activity.88 Copper, also required for bone formation, is a cofactor cal trials using vitamin K that showed increases in BMD and/or for the lysyl-oxidase enzyme.88 This enzyme forms collagen and reduction in fracture risk in volunteers who had bone loss from elastin cross-links from the essential amino acid lysine.88 anorexia nervosa, Parkinson's disease, biliary cirrhosis, and stroke and also in volunteers who were taking prednisone and leuprolide; in other volunteers, it increased the efficacy of bis- Strontium, an alkaline earth metal, has been studied for its phosphonate medications. ability to increase BMD and reduce fracture risk. Strontium IMCJ also published a thorough vitamin K review, written ranelate (SR) is a form of strontium salt from ranelic acid pat- by Lara Pizzorno and Joseph Pizzorno, ND, in the April-May ented by a French company. SR is well studied and currently 2008 issue (IMCJ 7.2:24-30) where they explain how vitamin K approved for the treatment of osteoporosis in most of Europe but aids bone health in a number of ways, including completing the is not yet approved in the United States. Animal studies have bone-building effects of vitamin D 's upregulation of osteo- shown it to have an affinity for bone, decreasing bone resorption blasts' expression of osteocalcin and inhibiting the differentia- and increasing bone formation in rats.89 A recent in vitro study tion of osteoclasts.
determined that SR affects bone through induction of osteoblas-togenesis.90 Several studies have evaluated the efficacy of SR in preventing and reversing osteoporosis in experimental animals In healthy bone, free radicals are used by osteoclasts to "chisel away at older bone,"78 which creates small holes in bone In 2002, results were published from a phase II, 2-year, random- that are filled by osteoblasts with new bone. As long as this is kept ized, multicenter, double-blind, placebo-controlled, dose-response in check, all is well. When the balance becomes skewed with too trial of SR for the treatment of osteoporosis (STRATOS).91 Participants many free radicals (ie, an inadequate intake of antioxidants), in the study were 353 nonobese, post-menopausal, osteoporotic however, osteoporosis may result. An Italian study compared the women between 45 and 78 years of age who were randomized to 1 of antioxidant status of 75 post-menopausal, osteoporotic women 4 groups (placebo, SR 0.5 g/d, SR 1.0 g/d, and SR 2.0 g/d). In addi- to 75 women without osteoporosis, ages 62 to 79 years, for 12 tion to supplemental strontium or placebo, all patients received months. Compared to controls, postmenopausal women with supplemental calcium (500 mg/d) and vitamin D (vitamin D , 800 osteoporosis had significantly lower levels of plasma vitamin A IU/d) "to ensure," as the researchers said, "that patients affected by (2.37 ± 0.22 vs 2.14 ± 0.22 μmol/L, respectively), plasma vitamin severe osteoporosis received a minimum level of active treatment." C (55.5 ± 13.1 vs 30 ± 3.7 μmol/L, respectively), plasma vitamin All women had at least 1 previous vertebral fracture (T4 to L5) and a E (62.8 ± 8.76 vs 46.7 ± 5 μmol/L, respectively), plasma uric acid lumbar T-score of -2.4 or less. The primary endpoint was lumbar (383.5 ± 63.7 vs 227.8 ± 34.6 μmol/L, respectively), plasma gluta- BMD, and the secondary outcomes included femoral neck BMD thione peroxidase (0.11 ± 0.01 vs 0.09 ± 0.01 mmol NADPH/ (FN-BMD), incidence of new vertebral deformities, and biochemical min/mil, respectively), plasma superoxide dismutase (31.34 ± markers of bone metabolism. Bone measurements were tested using 3.1 vs 24.22 ± 3.8 U/ml, respectively), and erythrocyte superox- dual-energy x-ray absorptiometry (DEXA) and were verified by iliac ide dismutase (3402 ± 505.8 vs 2265 ± 314.7 U/g hemoglobin, crest bone biopsies taken at months 12 and 24. respectively).46 All antioxidant concentrations correlated with By 12 months an increase in BMD was observed in all treat- femoral BMD; however, significant positive correlations were ment groups, with further increases at 24 months. FN-BMD also noted only for vitamin A (P<.01), vitamin C (P<.05), and plasma increased in the treatment groups but decreased in the placebo glutathione peroxidase (P<.05). group. By the end of the second year of the study, the incidence of Previous human studies have shown that vitamin C supple- new vertebral deformities, while having increased in the placebo mentation, especially in conjunction with calcium supplementa- group, decreased in the treatment groups. However, during the tion, and vitamin E protect against bone loss.79-81 In an animal second year, women receiving 0.5 g SR/day had a 0.51 (95% CI study, supplementation with N-acetylcysteine increased levels of 0.31; 0.84) relative risk of experiencing a new deformity, while the antioxidant glutathione.82 Although no randomized, con- women taking 2 g SR/day had a higher relative risk of 0.56 (95% trolled trial has been conducted that analyzed the effects of multi- CI 0.35; 0.89). The overall relative risk of a new deformity over the antioxidant supplementation on bone health, it is logical to con- entire 2-year period, compared to placebo, was 0.71 (95% CI 0.49; clude that increasing the body's antioxidants may help decrease 1.02) and 0.77 (95% CI 0.54; 1.09) in the SR 0.5 g/d and SR 2.0 the rate of loss of BMD. g/d groups, respectively. Urinary excretion of bone-resorption markers was decreased in all treatment groups, while alkaline phosphatase (an indicator of osteoblast activity) was increased. Osteoporosis risk is increased by low intakes of calcium,83,84 Although the fracture risk was greater in the higher treatment potassium,85 magnesium,85 and vitamin K86 and by low concen- group (2 g SR/d) versus the lower (0.5 g SR/day), the higher SR Integrative Medicine • Vol. 7, No. 6 • Dec 2008/Jan 2009
Neustadt and Pieczenik—Osteoporosis group experienced the greatest increases in BMD, about 3% per As baby boomers age, the healthcare system will likely be year. Adverse effects were mild to moderate, and the treatment overwhelmed by the financial and medical burden of treating was well tolerated in all treatment groups. osteoporotic fractures and the disability they create. Aggressive A second study evaluated the reduction in fracture risk in a treatment approaches that distinguish BMD from fracture risk phase III, randomized, double-blind, 3-year clinical trial utilizing and so identify and prevent fractures before they occur should be 2 g SR/d or placebo in 1442 postmenopausal women (mean age considered and implemented in clinics, by insurance companies, approximately 69 years) with osteoporosis.92 All volunteers also and as a matter of public policy.
received at lunchtime, dependent on dietary calcium intake, up to 1000 mg elemental calcium to ensure an intake of more than 1500 mg calcium daily, plus 400 to 800 IU vitamin D (form of vitamin John Neustadt, ND, is clinic director of Montana Integrative Medicine and
D not specified), depending on their baseline vitamin D president and CEO of Nutritional Biochemistry Inc (NBI), and NBI Testing and Consulting Corp (NBITC), all in Bozeman. Dr Neustadt has published more (25-hydroxyvitamin D) status. than 100 research reviews, is coauthor with Steve Pieczenik, MD, PhD, of the After 12 months, total vertebral-fracture risk decreased by book A Revolution in Health through Nutritional Biochemistry (iUniverse Inc, 49% in the SR group compared to placebo (P<.001), and the SR 2007), and is an editor of the textbook Laboratory Evaluations for Integrative and group also had a 52% reduction of symptomatic fractures (P=.003). Functional Medicine (Metametrix, 2008).
By the end of the 3-year study, BMD in the SR group increased over Steve Pieczenik, MD, PhD, trained in psychiatry at Harvard, has an MD from
baseline by 12.7% at the lumbar spine, 7.2% at the femoral neck, Cornell University Medical College and a PhD in international relations from and 8.6% at the total hip (P<.001 for all 3 sites). Also by study end, Massachusetts Institute of Technology. He is a board-certified psychiatrist and volunteers taking SR had a 41% lower risk of a new vertebral frac- was a board examiner in psychiatry and neurology. He is chairman of the boards ture than those in the placebo group (P<.001). The researchers of NBI and NBITC.
concluded that to prevent 1 patient from suffering a vertebral fracture, 9 patients would need to be treated for 3 years with SR. 50. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate A cautionary note should be inserted about SR. Strontium on risk of fracture in women with existing vertebral fractures. Fracture Intervention has an atomic mass greater than calcium. As such it attenuates Trial Research Group. Lancet. 1996;348(9041):1535-1541.
51. Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of rise- the X-rays from a DEXA scan to a greater extent than does calci- dronate on vertebral fractures in women with established postmenopausal osteopo- um.91 Unless the radiologist corrects for this, the DEXA scan will rosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int. 2000;11(1):83-91.
not provide an accurate measure of BMD.91 Additionally, the 52. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in post- form of strontium used in clinical trials (strontium ranelate) is menopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) not available in the United States. The form available in dietary supplements in the US is strontium citrate. Although the stron- 53. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N tium citrate form may be effective at improving BMD and Engl J Med. 2001;344(19):1434-1441.
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Neustadt and Pieczenik—Osteoporosis


Cresemba, isavuconazole

SUMMARY OF PRODUCT CHARACTERISTICS This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT

Pmed.1001236 1.12

Nevirapine- Versus Lopinavir/Ritonavir-Based InitialTherapy for HIV-1 Infection among Women in Africa: ARandomized Trial Shahin Lockman1,2,3*, Michael Hughes2, Fred Sawe4, Yu Zheng2, James McIntyre5, Tsungai Chipato6, Aida Asmelash3, Mohammed Rassool7, Sylvester Kimaiyo8, Douglas Shaffer4, Mina Hosseinipour9, Lerato Mohapi10, Francis Ssali11, Margret Chibowa12, Farida Amod13, Elias Halvas14, Evelyn Hogg15,