RevisióN Osteoporosis

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  • 1. Alternative Medicine Review Volume 12, Number 2 2007 Review Article Osteoporosis: Integrating Biomarkers and Other Diagnostic Correlates into the Management of Bone Fragility R. Keith McCormick, DC, CCSP Introduction Over 50 percent of women and 13 percent of Abstract men over age 50 will sustain an osteoporotic-related Bone health, characterized by its mass, density, and micro- fracture1 and over 10 million Americans have been di- architectural qualities, is maintained by a balanced system of agnosed with osteoporosis,2 at a direct medical cost of remodeling. The lack of these qualities, caused by an uncoupling 17 billion dollars.3,4 In addition to improving awareness of the remodeling process, leads to bone fragility and an of bone health and achieving peak bone mass, it is im- increased risk for fracture.The prime regulator of bone remodeling portant to use targeted nutrition. Although it has been is the RANK/RANKL/OPG system. The common origin of both shown that calcium supplementation slows postmeno- bone and immune stem cells is the key to understanding this pausal bone loss5 and may prevent fragility fractures,6,7 findings from the Women’s Health Initiative clinical system and its relationship to the transcription factor nuclear trial demonstrate the shortcomings of a limited nutri- factor kappaB (NFkB) in bone loss and inflammation. Via this tional approach to bone health. This study shows that coupled osteo-immune relationship, a catabolic environment giving calcium and vitamin D supplements did not re- from heightened proinflammatory cytokine expression and/or duce hip fractures and only minimally increased bone a chronic antigen-induced activation of the immune system mineral density (BMD) in postmenopausal women.8,9 can initiate a “switch-like” diversion of osteoprogenitor- At the same time, pharmacological intervention has not cell differentiation away from monocyte-macrophage and proven particularly successful in treating bone loss.10 osteoblast cell formation and toward osteoclast and adipocyte Osteoporosis prevention should begin long formation. This disruption in bone homeostasis leads to before menopause. Failure to achieve optimal nutri- increased fragility. Dietary and specific nutrient interventions tion from birth (or before) and through the years of can reduce inflammation and limit this diversion. Common adolescence and early adulthood when peak bone mass laboratory biomarkers can be used to assess changes in is attained can result in increased fracture risk later in body metabolism that affect bone health. This literature review life.10 Bone fragility may already have been determined at conception11 and been modulated in utero via genet- offers practical information for applying effective strategic ics and the negative influences of excessive oxidative nutrition to fracture-risk individuals while monitoring metabolic stress,12 low levels of maternal 25-hydroxyvitamin D,13 change through serial testing of biomarkers. As examples, or other contributing factors. the clinician may recommend vitamin K and potassium to reduce hypercalciuria, a-lipoic acid and N-acetylcysteine to reduce the bone resorption marker N-telopeptide (N-Tx), and R. Keith McCormick, DC, CCSP – Stanford University, BA in Human Biology, dehydroepiandrosterone (DHEA), whey, and milk basic protein 1978; National College of Chiropractic, DC and BS in Human Biology, 1982; Logan College of Chiropractic, Certified Chiropractic Sports Physician (CCSP), (the basic protein fraction of whey) to increase insulin-like 1987; Private Practice, 1982-present. Correspondence address: 145 Old Amherst Road, Belchertown, MA 01007 growth factor-1 (IGF-1) and create a more anabolic profile. Email: Keith@mccormickdc.com (Altern Med Rev 2007;12(2):113-145) Page 113 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 2. Alternative Medicine Review Volume 12, Number 2 2007 Osteoporosis Biomarkers Bone density often begins to decline prior to Bone Fragility: A Term for Defining mid-adulthood,14 before a woman’s estrogen levels be- Increased Fracture Risk Based on the gin to recede.15,16 A decline in skeletal integrity may stem from adverse environmental conditions such as Quantity and Quality Components of smoking, inactivity, or gastrointestinal inflammation Bone and malabsorption; however, for a patient at risk for In 1994, a World Health Organization fragility fracture, strategic nutritional therapy can have (WHO) study group defined osteoporosis as “a syste- a major impact in improving bone health.17 Although mic skeletal disease characterized by low bone mass and estimates suggest 50 percent of the variance in peak micro-architectural deterioration of bone tissue, with a bone mass is due to genetics,18 it is also estimated that consequent increase in bone fragility and susceptibility 30-50 percent of the genetic factors that influence bone to fractures.”19 This definition was further characterized strength can be affected by the environment in which as having a BMD T score of at least 2.5 standard devia- bone is immersed. The use of biomarkers (laboratory tions below a healthy, young, white female. Table 1 out- measures of biological processes) facilitates targeted lines WHO T-score classifications. The measurement nutritional intervention and is a valuable, underutilized of BMD (the amount of mineralized tissue in a scanned clinical tool. For example, serial testing of urine organic area) is most commonly attained through dual-energy acids can assess the efficacy of carnitine supplementa- x-ray absorptiometry (DXA) and is an areal assessment tion for improving fatty acid metabolism, while efficacy of bone density designated in g/cm2. Instead of using of a-lipoic acid can be assessed by observing reduction BMD for evaluating a patient’s bone loss, a T score is of bone resorption markers. used to convert g/cm2 from different scanners to a com- To be effective, analysis of bone health and mon scale and also to assess the prevalence of osteopo- treatment of bone fragility must be sufficiently sophis- rosis within a population. “This value captured 30% of ticated to take all these factors into account. Other than the postmenopausal population with a T score of -2.5 histological examination of trans-ilial bone biopsy spec- or below at the hip (femoral neck), anterior-posterior imens, there is no direct way to assess bone quality in lumbar spine, or forearm that matched the lifetime risk the clinic. Physicians therefore rely mainly on BMD for for fracture at any of these three skeletal sites in these diagnosis and treatment efficacy and fail to recognize populations.”20 “Osteopenia” refers only to a loss of bone the benefits of using common biomarkers in the man- mass (T score -1.0 to -2.4) and, unlike the term “osteo- agement of patients with bone fragility. porosis,” does not refer to any aspects of bone quality. The current emphasis on BMD in the diag- nosis and treatment of osteoporosis limits awareness of the importance of bone quality. Although collagen matrix mineralization contributes substantially to bone Table 1. World Health Organization Classification of T Score Normal BMD ≥ -1.0 Low bone mass (osteopenia) BMD > -2.5 and < -1.0 Osteoporosis BMD ≤ - 2.5 Severe (established) osteoporosis BMD ≤ - 2.5 with history of fragility fracture Page 114 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 3. Alternative Medicine Review Volume 12, Number 2 2007 Review Article strength (stiffness and resistance to structural failure) Secondary findings from the Improving Mea- and low bone mass is associated with increased risk for surements of Persistence of Actonel Treatment (IM- fracture,21,22 BMD by itself is not an accurate predic- PACT) trial showed 38 percent of subjects, ages 65-80, tor of strength,23 and the terms cannot be used inter- with a diagnosis of osteoporosis had no risk factors.32 changeably. Quality aspects of bone, such as size, shape, This statistic is important to consider when evaluating integrity of collagen fibers, thickness and connectedness the individual patient. Optimal fracture-risk assessment of trabeculae, and the rate of bone turnover also affect in the individual patient can be achieved by using diag- the overall strength of bone.24 For this reason, the term nostic correlates from DXA and currently available bio- “bone fragility” is used in this article to emphasize the technology in a translational medical approach. Using importance of both the quantity and quality aspects of bone-related biomarkers and other laboratory tests not bone in the determination of fracture risk. The health traditionally associated with bone health can improve of bone, and therefore its strength and fracture risk, is therapeutic management and identify individuals with determined by both density and quality components. elevated fracture risk independent of reduced BMD. It has become evident that the increase in Once identified, these patients will benefit from diet BMD seen with bisphosphonate therapy for osteoporo- and nutritional intervention to improve bone health sis is only weakly associated to overall fracture-risk re- and reduce fracture risk. duction25-27 and only slightly improves bone strength.28 Early reduction in fracture risk by bisphosphonates is Pathophysiology of Osteoporosis and achieved through stabilization of only one bone quality Bone Fragility component – a reduced number of resorption sites.29 De- Bone health is maintained by a balanced remod- spite these findings, physicians have been slow to grasp eling process that ensures the continual replacement of the importance of bone quality. A lack of non-invasive old bone, weakened by microfractures, with new bone. tools for assessing the compositional quality of bone in This is a coupled process involving bone resorption by the clinical setting is the root of this failure. In addition, osteoclasts and new bone formation by osteoblasts. because bisphosphonates improve BMD, practitioners Failure to reach peak bone mass or the uncoupling of believe the problem has been addressed and other fac- remodeling can result in bone fragility. tors contributing to bone fragility are ignored. Practitioners, as well as the general public, have adopted the erroneous belief that the numbers seen on The Role of RANK/RANKL/OPG and DXA reports equate to an assessment of bone strength T Cells in Bone Remodeling and overall bone health. Over-emphasis on BMD is Although estrogen is the key sex hormone gov- further complicated by questions concerning potential erning bone homeostasis, the primary regulator of bone sources of error in serial DXA interpretation30 and, remodeling is now being recognized as the RANK/ therefore, in the ability of DXA to help assess efficacy RANKL/OPG system (defined below).33 This osteo- of therapy.31 Despite concerns of accuracy and inabil- immunological system determines the success or failure ity to assess bone quality, DXA technology remains the of bone homeostasis. The common origin of bone and primary diagnostic tool in osteoporosis management immune stem cell is the key to understanding this sys- because it is inexpensive and readily accessible. tem and the physiology of bone loss. It is also the key to Currently the WHO is designing an absolute applying effective nutritional therapy for the inflamma- fracture-risk model that will help clinicians determine tory, catabolic-based increase in bone fragility. who is at risk and when drug therapy should be initi- Bone-resorbing cells (osteoclasts) and cells of ated. Although this may be an improvement to current the immune system both originate in the bone marrow fracture risk assessment, it is essential to keep in mind from hematopoietic cells. Osteoclasts develop from pre- the pitfalls of predicting bone loss in a particular patient cursors of the mononuclear monocyte-macrophage cell on the basis of overt characteristics such as sex, age, and line after stimulation by macrophage colony-stimulat- lifestyle. ing factor (M-CSF) and receptor for activated nuclear- factor kappa B (RANK) ligand (RANKL) (Figure 1).34 Page 115 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 4. Alternative Medicine Review Volume 12, Number 2 2007 Osteoporosis Biomarkers Bone-forming cells (osteoblasts) are of mes- enchymal origin and share a common precur- Figure 1. Osteoclasts, Immune Cells, and RBCs are Derived sor cell with adipocytes. During normal bone from Marrow Hematopoietic Stem Cells remodeling, marrow stromal cells and osteo- blasts produce RANKL, which binds to the transmembrane receptor RANK on osteoclast Bone Marrow precursors and induces differentiation and ac- tivation (Figure 2).35 This occurs through the transcription factor, nuclear-factor kappa B Hematopoietic Erythroid (NFkB), which is responsible not only for ac- Stem Cell Progenitor tivating osteoclastogenesis but also the body’s M-CSF inflammatory response. Both osteoclast differ- entiation and the inflammatory process occur RANKL via regulation of interleukin-6 (IL-6). Myeloid Progenitor Lymphoid RBC The major role cytokines play in bone Progenitor remodeling is demonstrated by the fact that Osteoclast receptors for the proinflammatory cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis Dendritic factor-alpha (TNF-a) are present on both os- Cell T Cell Macrophage teoclast precursor cells and mature osteoclasts. Estrogen exhibits its nuclear regulatory effects by inhibiting IL-6 activation of NFkB during The pluripotent hematopoietic stem cell di erentiates into myeloid, lymphoid, bone remodeling.36 Osteoblasts also produce and erythroid progenitor cells. The commonality of origin and the factors that osteoprotegerin (OPG), a soluble decoy recep- govern their di erentiation are keys to understanding the relationship between immune regulation and accelerated osteoclastic bone resorption. tor that blocks RANKL and maintains control of the remodeling process. OPG is vital to the success of the RANK/RANKL/OPG system of bone homeostasis. Figure 2. Osteoblasts, Cartilage, and Adipocytes are Derived from Marrow Mesenchymal Stem Cells Chronic Immune Activation and the Uncoupling of Remodeling Osteoblasts RANKL is also produced by activated T cells. With reduced estrogen levels and/or chronic or recurrent immune activation from either sys- Mesenchymal temic or gastrointestinal origin, there may be a Stem Cell PPAR reduction in the body’s natural ability to limit the production of RANKL.37 This results in increased osteoclast activation through a “switch-like” diver- sion of osteoprogenitor-cell differentiation away Adipocyte Osteoblast from monocyte-macrophage-cell development and Cartilage Cells toward osteoclastogenesis. Osteoclastic activity, in- duced by proinflammatory cytokines and activated T cell-induced RANKL, is thought to be modu- Cytokines for Remodeling lated by the action of interferon gamma (IFN-γ) on tumor necrosis factor receptor-associated factor Dysregulation of common precursor-cell di erentiation is the link between obesity and low bone density, the two most common 6 (TRAF-6).38 TRAF-6 is a RANK adaptor pro- disorders in the United States. tein that mediates NFkB activation (Figure 3).39,40 Page 116 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 5. Alternative Medicine Review Volume 12, Number 2 2007 Review Article This uncoupling of the remodeling process results in bone loss. In studies using mice, chronic antigenic load Figure 3. RANK/RANKL/OPG Osteo- with T-cell activation and production of reactive oxygen immunological System of Bone Homeostasis species (ROS) must be present for low estrogen levels to cause bone loss.44 It appears that reducing antigenic load and oxidative stress may be equally as important as estrogen in maintaining bone health. Osteoblast Stromal Cell Oral Tolerance and Bone Health Oral tolerance, the muted immunological response to harmless gut antigens, depends on the M-CSF RANKL presence of commensal microorganisms and an intact Osteoclast healthy gut wall. Epithelial cell integrity is maintained OPG by the presence of beneficial organisms such as Lactoba- RANK cillus and Bifidobacteria that do not elicit an inflamma- TRAF6 tory response. When normal gastrointestinal flora are NF B maintained, immunological self-tolerance through the Progenitor activation of T-regulatory cells (Tregs) favors a non-in- flammatory T-helper 2 (Th2) dominant response to gut microbes.45 Pathogenic bacterial or fungal overgrowth causes inflammation and increased gut permeability Macrophage that reduces oral tolerance. Focus on the traditional os- or teo-endocrine explanation for bone homeostasis fails to Dendritic Cell acknowledge the important role of the immune system in remodeling and the possible role of oral tolerance in maintaining bone health. It is now understood that a high systemic antigen load of bacterial or viral origin This modulating capacity of IFNγ over RANKL is in- and/or a loss of oral tolerance due to pathogenic micro- fluenced by both vitamin D and estrogen. bial overgrowth (long suspected as major contributing Aging leads not only to a reduction in sex-hor- factors in other chronic degenerative diseases) may also mone production, but also to an increase in the general contribute to the pathogenesis of bone loss. level of proinflammatory cytokines and diminution of Estrogen normally helps preserve bone by immune system function. In vivo, free radicals have been enhancing macrophage production of transforming shown to increase bone resorption,41 and oxidative stress growth factor β (TGF-β) and limiting CD4+ T-cell ac- reduces BMD in humans.42 These environmental and/ tivation. Reduced levels of estrogen result in an increase or age-related catabolic stressors contribute to normal in antigen-presenting cells and a reduction in TGF-β bone loss. But when there is chronic, elevated antigenic and Tregs. This leads to T-cell activation and produc- load or excessive oxidative stress, which increases pro- tion of proinflammatory cytokines and RANKL, which inflammatory cytokine-induced RANKL, the activation stimulates osteoclastogenesis (Figure 4). By improving of this “switch” in osteoprogenitor-cell differentiation gut health and oral tolerance, antigen presentation to T may, independent of age, adversely affect the balance of cells is reduced, TGF-β production is maintained, Tregs bone remodeling. It is in this abnormal state that chronic are enhanced, and RANKL-induced osteoclastogenesis immune activation may alter IFN-γ modulating capac- is limited, even with reduced levels of estrogen. ity. When estrogen is deficient, causing RANKL levels to increase, the body’s natural ability to limit the tran- scription factors TRAF-6 and NFkB may be reduced and IFN-γ may exert a pro-osteoclastogenic effect.43 Page 117 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 6. Alternative Medicine Review Volume 12, Number 2 2007 Osteoporosis Biomarkers Figure 4. Chronic Immune Activation Leads to Bone Loss TGF- Osteoblast or Preosteoblast TNF- RANKL OPG (Inhibits) TNF- Osteoclast IFN- RANKL RANK T Cell TRAF6 NF B Progenitor (Inhibits) IL-1, IL-6, TNF- (Inhibits) Treg Macrophage or Dendritic Cell Activation of T cells is necessary for osteoclast di erentiation. RANKL activation of NF B through the RANK adaptor protein, TRAF6, increases osteoclastogenesis from progenitor cells. IFN- can either increase or limit bone resorption through modulation of this cascade. This "fail safe" mechanism, under normal circumstances, limits bone resorption. But with chronic T-cell activation and a predominate Th1 response, IFN- no longer limits osteoclast activation and bone resorption increases. Estrogen increases vitamin D receptor activation and calcitonin release. It also increases osteoblast release of TGF- , IGF-1 and OPG, which limits M-CSF and RANKL and increases osteoclast apoptosis. With reduced estrogen levels, TGF- decreases and antigen presentation to T cells increases the release of RANKL and TNF- , diverting progenitor cell di erentiation toward osteoclastogenesis. Vitamin D and normal gut ora help preserve tolerogenic dendritic cells and reduce activation of RANKL-induced osteoclastogenesis. T-Helper 1 (Th1) Dominance osteoclastogenesis, more research is needed to deter- Imbalance in the Th1/Th2 adaptive immune mine whether early maturational and/or chronic immu- response initiated by antigenic stress may play a part in nological stressors contribute to excessive bone loss in specific cases of osteoporosis.43 With T-cell activation later years. In addition to nutrient malabsorption, high now known to have a major role in RANKL-induced antigen load from food allergies or intestinal microbial overgrowth may contribute to bone loss. Page 118 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 7. Alternative Medicine Review Volume 12, Number 2 2007 Review Article Mature osteoclasts gain access to bone surfaces cause (e.g., insulin/glucose imbalance, toxicity, or gut only after mononucleated preosteoclasts have trav- pathogenic microflora), could reduce proinflammatory eled from the circulatory system to the bone, possibly cytokine-induced chronic inflammation and T-cell ac- through mechanisms involving transendothelial migra- tivation. tion.46 The gut-associated lymphoid tissue normally provides an immunological barrier against disease. Involution of Thymus Gland and the Beginning When this barrier becomes compromised by endothe- of Bone Loss lial hyperpermeability secondary to food allergy or bac- Reduced oral tolerance may be a factor in the terial overgrowth, nutrient absorption is reduced, and a apparent coincidence between thymus gland involution loss of oral tolerance can initiate a gastrointestinal-im- (and subsequent reduction of naive T-cells) and the on- munological stressor of the bone remodeling process. set of bone loss that begins in humans in their mid-30s. RANKL regulates not only the function of Although BMD does not usually decrease significantly osteoclasts but also that of dendritic cells (profession- until menopause, accelerated bone loss can commence al antigen-presenting cells). In chronic inflammation, at an earlier age for some individuals. Reduced numbers RANKL promotes dendritic cell survival and the ex- of naive T cells from chronic systemic inflammation or pression of proinflammatory cytokines.47 As the gut is antigen overload from the gut leads to oligoclonal T-cell overrun by pathogens, professional antigen-presenting expansion and increased T-cell senescence.51 Senescence cells, through the activation of toll-like receptors and reduces a T cell’s ability to produce IFN-γ33 and is a sign C-type lectin receptors, are no longer able to silence of immune aging. immune activation48 and release proinflammatory cyto- The primordial thymus developed as a bud on kines that activate T cells and reduce Tregs. This an- the immature digestive tract, providing embryological tigenic stress leads to a Th1-dominant, cell-mediated evidence of the uniquely co-dependent and interrela- immune system49,50 with increased RANKL, reduced ted functions of the thymus gland and gastrointestinal IFN-γ, and a possible uncoupling of bone remodeling. tract.52 As an infant grows, the function of the thymus is to relieve the gut of its primordial function of lym- Toll-like Receptors phopoiesis.52 With involution of the thymus, the adult The production of gut-related proinflammato- gastrointestinal tract remains the source of at least 75 ry cytokines is reduced by the maintenance of a healthy percent of the body’s immune cells;53 therefore, it is in gut flora. Toll-like receptors are transmembrane recep- the gut that an adult’s immune health is maintained or tors found on macrophages, dendritic cells, and some lost. As an individual ages, antigen load often increases epithelial cells, and play an integral role in maintaining and oral tolerance decreases, leading to reduced levels of oral tolerance. These receptors recognize the molecular IL-2 (necessary for T-cell proliferation and differentia- patterns of bacteria and elicit an inflammatory, destruc- tion into activated [effector] cells) and IFN-γ, and ulti- tive response to pathogenic microbes and a tolerogenic mately to a greater cache of RANKL-expressing (and response to commensal bacteria. thus osteoclast-activating) memory cells harbored in An example of how a disease-related genetic the bone marrow. polymorphism can be influenced through the reduction of metabolic stressors can be seen in the case of toll-like Patient Evaluation and IL-1 receptors. Because the cytoplasmic portion of Osteoporosis is a polygenic, multifaceted, met- the toll-like receptor is similar to that of the IL-1 recep- abolic disorder necessitating a complete understanding tor, an individual suffering from chronic dysbiosis and of its etiopathology. Even after the initial thorough con- also carrying the polymorphism for the IL-1 receptor sultation, physical examination, DXA scan, vertebral antagonist gene could, in theory, be susceptible to an fracture assessment (VFA) or other spinal imaging increased diversion or “switch” of cells from the mono- (if appropriate), and laboratory evaluation, therapeu- cyte-macrophage cell line to form osteoclasts. A reduc- tic intervention for a patient with increased fracture tion of antigen load and oxidative stress, no matter the risk should entail follow-up serial testing and ongo- Page 119 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 8. Alternative Medicine Review Volume 12, Number 2 2007 Osteoporosis Biomarkers Consultation and Physical Examination Table 2. Risk Factors for Fragility Fracture Bone fragility is associated with multiple risk factors (Table 2), among the most important being ad- vancing age, female gender, low body weight, low BMD, Advanced age prior fragility fracture, early menopause, eating disor- ders, and maternal history of osteoporosis.54 Patient Personal history of fracture related to history should include assessment of these risk factors mild-to-moderate trauma as an adult as well as looking for secondary factors that could po- tentially contribute to bone loss, such as malabsorption Family history of hip fracture syndromes (Table 3), disease processes, or the previous or current use of certain medications. Celiac disease and Low body weight lactose intolerance are common conditions causing re- duced calcium absorption and increased bone loss.55 In- flammatory diseases, endocrinopathies, primary biliary Weight loss Loss of height Table 3. Biomarkers for Malabsorption Late onset of sexual development Cholesterol —— low Poor health Total protein —— low Gonadal hormone deficiency Albumin —— low Poor nutrition Calcium —— low Use of certain medications Vitamin D —— low Smoking Anemia (hypochromic/microcytic Alcoholism or macrocytic) Inadequate physical activity Frequent falls cirrhosis, eating disorders, environmental toxicity,56,57 cancer, and the loss of estrogen are all implicated in the development of osteoporosis. ing decision making to fine-tune treatment. Given the Many common medications can increase bone complexity of the disease, relying solely on biannual loss. Glucocorticosteroids (e.g., prednisone), even in dos- DXA exams to monitor treatment efficacy may not be es as low as 2.5 mg/day, are known to increase fracture sufficient. risk.58 As observed in A Diabetes Outcome Progression Trial (ADOPT), thiazolidinediones (e.g., Avandia® and Actos®) for type 2 diabetes, in addition to their poten- tial for liver toxicity, can suppress osteoblast cell dif- ferentiation in favor of adipocytes from mesenchymal Page 120 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 9. Alternative Medicine Review Volume 12, Number 2 2007 Review Article precursor cells, and were linked to increased fracture laboratory based or point-of-care tests, which could be risk in women.59 Aromatase inhibitors for breast can- linked to drug therapy. The N-telopeptide (N-Tx) test cer (e.g., Arimidex®) and luteinizing-hormone releasing for assessing bone resorption activity is a good example hormone agonist therapy for prostate cancer (e.g., Lu- of a theranostic development for bisphosphonate use pron®) increase bone loss. Depot medroxyprogesterone in the treatment of osteoporosis. Common laboratory acetate for birth control60 and heparin therapy during biomarkers such as urine calcium or salivary cortisol pregnancy61 both reduce bone density. The CaMos can also be used as theranostic indicators for nutritional study found daily use of cyclooxygenase-2 (COX-2) intervention and its therapeutic efficacy. The 2004 Bone inhibitors decreased load-induced bone formation in Health and Osteoporosis: A Report of the Surgeon General men. On the other hand, women in the study gained supports the use of laboratory bone-turnover markers bone density with COX-2 inhibitor use; however, the to assess treatment effectiveness.65 The use of these and bone protective effect was lost when COX-2 inhibi- other biomarkers as foundational tools in caring for tors were combined with exogenous estrogen therapy.62 fracture-risk patients has potential for optimizing bone Proton-pump inhibitors have recently been shown to health and reducing fracture morbidity. increase hip fractures.63 Anticonvulsants such as pheno- Minimal laboratory screening for patients with barbitone, phenytoin, and carbamazepine are known to either low bone density (T score < -1.0) or risk fac- interfere with vitamin D metabolism leading to hypo- tors that arouse concern would include complete blood calcemia, low 25-hydroxyvitamin D (25(OH)D), and count (CBC), chemistry profile, functional metabolic bone loss.64 profile of urine organic acids, urine pH, urine calcium/ In addition to gaining important information creatinine ratio, serum 25-hydroxyvitamin D, serum on risk factors and a subjective account of nutritional calcium and phosphorus, tissue transglutaminase anti- history from the patient, a comprehensive physical body, N-Tx, thyroid-stimulating hormone (TSH), es- examination may reveal clues directly relevant to the trogen, testosterone, and sex hormone-binding globulin patient’s bone health status. A patient may complain of (SHBG). An extended assessment may include immu- muscle pain or they may have sensitive shins and ster- noelectrophoresis, insulin-like growth factor-1 (IGF- num seen with osteomalacia – both associated with a 1), homocysteine, dehydroepiandrosterone (DHEA), vitamin D deficiency. Magnesium deficiency can cause follicle-stimulating hormone (FSH), parathyroid hor- muscle cramping, constipation, or depression. Steat- mone (PTH), vitamin B12, cortisol, food-allergy test- orrhea may indicate intestinal microbial overgrowth ing, stool analysis, salivary secretory IgA, and others. or liver dysfunction and a reduction in vitamin D and The following summary of laboratory tests is calcium absorption. Fingernail changes may indicate a intended only as a brief guide to the use of theranostics mineral deficiency. Examination of the oral cavity may in the management of patients with low bone density reveal a white coated tongue indicative of Candida in- or high fracture risk. It is not intended as a diagnostic fection, angular cheilitis or tooth discoloration of celiac outline but as a way to introduce how biomarkers can disease, increased caries from low oral pH and poor be used to assess the need for, and efficacy of, nutritional dental mineralization, or the receding, red, swollen, and care in patients with bone fragility. Other than the bone boggy gums of periodontal disease that can be associ- resorption and formation tests, the biomarkers discussed ated with osteoporosis. here are not specific to bone and can be used effectively in managing bone fragility only when employed in the Laboratory Evaluation broader context of obtaining overall health. There are Theranostics, the use of serial laboratory stud- many conditions that lead to bone loss, some extremely ies for diagnosing and tailoring individual treatment, serious and life threatening such as multiple myeloma. can help define the etiology of bone loss and also guide If the physician has any reason to suspect the diagnosis a clinician’s specific nutritional intervention program. of osteoporosis is secondary to another disease process, The term theranostics was first used by the pharmaceu- the patient should be referred to an endocrinologist for tical industry to describe specific diagnostic tests, either further evaluation. Page 121 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 10. Alternative Medicine Review Volume 12, Number 2 2007 Osteoporosis Biomarkers Specific Laboratory Tests Dpd levels are influenced by muscle-collagen CBC and Chemistry Profile breakdown.10 Because N-Tx is more sensitive to change A complete blood count (CBC) and chemis- in bone metabolism than is Dpd,78 using serial testing try profile provide the clinician with a general survey of Dpd to evaluate for therapeutic efficacy may not pro- of multiple organ systems. These tests often contain a vide as useful an indicator as N-Tx. The resorption test wealth of clues that may be overlooked as borderline- C-telopeptide (C-Tx) is a serum marker for C-terminal low or -high results. For example, a mild decrease in al- telopeptide of type-1 collagen used predominately in bumin coupled with hypocalciuria may indicate malab- Europe. sorption;66 mild hypocalcemia can indicate magnesium deficiency;67 anemia may be related to celiac disease and Formation Markers resulting malabsorption of bone-building nutrients;68 Currently, osteoblastic bone formation can be and a low red blood cell (RBC) count may be secondary measured clinically using three different tests – serum to the effects of elevated proinflammatory cytokines69 osteocalcin, serum bone-specific ALP, and serum intact or the reduced hematopoietic capability of the osteopo- N-terminal propeptide of type-1 procollagen (P1NP). rotic patient’s fat-infiltrated bone marrow.70,71 Elevated levels of osteocalcin, bone ALP,79,80 and P1NP Alkaline phosphatase (ALP) is an enzyme are seen with increased bone remodeling and bone loss. found in bone, liver, intestine, kidneys, and placenta. Al- Bone ALP and P1NP are considered early markers of though it is an indicator of osteoblastic activity, ALP is formation, while osteocalcin, which is greatly influenced not specific to bone tissue and is therefore not typically by genetics,81 is a later marker of osteoblastic activity; used in the management of osteoporosis. ALP may be osteocalcin, although related to fracture risk,82 is a less normal or increased in postmenopausal women72 and responsive indicator. Although bone ALP is influenced may be reduced in celiac disease, hypothyroidism, per- by genetics, it remains an excellent formation marker nicious anemia, or zinc deficiency.73 Elevated ALP levels for determining osteoclastic over-suppression in pa- may also be an indication of cancer metastasis to the tients using bisphosphonate therapy.83 Osteocalcin and liver or bone. bone ALP have been shown to increase with vitamin K supplementation.84 Serum concentration of P1NP is directly pro- Bone-Turnover Biomarkers portional to the amount of new collagen produced by Resorption Markers osteoblasts.85 P1NP is useful for assessing bone turn- Bone resorption markers (e.g., urinary N-Tx over in postmenopausal women86 and is the best marker and deoxypyridinoline [Dpd]) reflect the level of os- for monitoring patients on teriparatide (recombinant teoclastic activity in the bone-remodeling process. Ac- human PTH) therapy.87 celerated osteoclastic activity increases bone turnover and is associated with low bone mass in both pre- and postmenopausal women.74 Elevated levels of resorption Metabolic Functional Assessment markers indicate increased osteoclastic activity and a Metabolic function assessment, through the higher risk for osteoporotic hip fracture, independent of use of urine organic acids, can help identify nutrient- BMD.75,76 Even when BMD is not in the osteoporotic related inadequacies in the metabolism of fats, carbo- range, increases in urine N-Tx (cross-links of N-termi- hydrates, and amino acids, and can be useful for the nu- nal telopeptide of type-1 collagen) and/or Dpd indicate tritional management of degenerative catabolic diseases increased osteoclastic-bone resorption and risk for frac- such as osteoporosis. Biomarkers for oxidative damage ture.66 A decrease in N-Tx, especially when monitored and intestinal dysbiosis can also illuminate potential serially, can be used as an early predictor of reduced underlying causes of osteoporosis. bone resorption with stabilization or increase of bone mass in response to treatment.77 Page 122 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 11. Alternative Medicine Review Volume 12, Number 2 2007 Review Article Urine Organic Acids Organic acid testing can also help identify re- Osteoporosis is not just a disease of deficiency; duced oxidative phosphorylation of mitochondrial bio- it is a catabolic disease with high correlation to diabe- energetics, which is “the unifying concept” of chronic tes, Alzheimer’s disease, and cardiovascular disease. age-related disease.91 Uncoupling of mitochondrial Similarities among these degenerative diseases include function leads to decreased energy for daily activity and chronic low-level inflammation and reduced mitochon- reduced muscle protein synthesis17 of sarcopenia often drial bioenergetics. Testing with urine organic acids can seen in patients with osteoporosis. The loss of muscle signal the presence of an inflammatory catabolic physi- mass and strength due to reduced mitochondrial func- ology. For example, elevated levels of urine lactate or the tion is not only intimately correlated to bone loss but ketone body, β-hydroxybutyrate, may indicate the cata- also contributes to an increased risk of falling, the major bolic profile of chronic metabolic acidosis from poor risk factor for fragility fractures.21 glucose utilization.88 In the borderline-anemic osteoporotic patient, Another indication of chronic inflammation reduced oxygen supply (hypoxia) secondary to poorly and immune system activation is demonstrated by al- vascularized fatty bone marrow leads to hypoxia, local tered levels of organic acid intermediates from the acidosis,92 and may stress mitochondrial energy produc- kynurenine pathway of tryptophan metabolism. The tion. Hypoxia not only reduces an individual’s strength intermediate, xanthurenic acid (XA), is used to iden- and energy level (leading to incoordination and falls), tify pyridoxine deficiency (vitamin B6 is a cofactor for but it has also been shown to increase osteoclastic bone several enzymes in the kynurenine pathway and a defi- resorption in vitro.93 ciency raises XA levels).88 Recently, other intermediates Testing for cellular energy function can iden- have been identified as contributors to various disease tify inefficiencies in the processing of food for the pro- processes, including osteoporosis.89 Stone and Darling- duction of adenosine triphosphate (ATP). The urine ton review the involvement of pathway intermediates markers citrate, cis-aconitate, isocitrate, a-ketogluta- – kynurenine, kynurenic acid (KynA), anthranilic acid rate, succinate, fumarate, and malate are intermediates (AA), 3-hydroxyanthranilic acid (3HAA), XA, and of the oxygen-requiring, mitochondrial citric acid cycle. quinolinic acid (QUIN) – in modulating glutamate re- Abnormal levels of these intermediates may indicate ceptors, activating NFkB, regulating cell proliferation, energy production inefficiencies as a result of polymor- and controlling microbial invasion and modulation of phism-related enzymatic dysfunction or deficiencies in the T-cell response by professional antigen-presenting B-complex vitamins, coenzyme Q10, or a-lipoic acid cells. When macrophages are stimulated by IFNγ, the – cofactors necessary for metabolism.88 In either case, initiating enzyme indoleamine-2,3-dioxygenase (IDO) urine organic acid testing can identify the need for spe- for the kynurenine pathway is activated. IDO reduces cific nutritional supplementation and help improve en- T-cell activation and is modulated by estrogen, TGF-β, ergy production. and proinflammatory cytokines.89 Forrest et al observed reduced blood levels of 3HAA and increased AA in pa- Markers of Oxidative Damage tients with osteoporosis. Because both XA and 3HAA Oxidative damage from free radicals is a major are metabolites of AA, the levels of these two biomark- contributing cause of degenerative diseases and, spe- ers correspond. Patients with osteoporosis demonstrate cific to osteoporosis, to the increase in osteoclastogen- a shift from 3HAA and XA toward AA. Reduced levels esis and subsequent bone loss. ROS, among the most of 3HAA and XA lead to reduced QUIN and, there- damaging free radicals, are constantly produced during fore, a reduced QUIN/KynA ratio. Bone cells have glu- mitochondrial respiration. Grassi et al demonstrated in tamate receptors sensitive to kinurenines, and altered vivo that ROS are necessary for bone loss to occur in levels appear to have direct effects on bone homeosta- estrogen-deficient mice.44 Thus, the use of biomarkers sis.90 The urine organic acids KynA, XA, and QUIN to identify patients with oxidative stress may be helpful are readily observable biomarkers. in managing osteoporosis. Urine or serum lipid perox- ides and urine 8-hydroxy-2-deoxyguanosine (a product Page 123 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 12. Alternative Medicine Review Volume 12, Number 2 2007 Osteoporosis Biomarkers of oxidative damage to DNA) are biomarkers that indi- are tapped to maintain normal pH.96 When NEAP be- cate increased oxidative stress.88 By reducing their levels comes chronically higher than the dietary base load, ion in the low bone-mass patient, the physician may also be exchange at the bone membrane becomes insufficient limiting mechanisms that lead to RANKL-induced os- and calcium salts from bone matrix are tapped. teoclastogenesis and Peroxisome Proliferator-Activated Acidosis is caused by poor diet, excessive pro- Receptor-gamma- (PPARγ-) induced reduction of os- tein intake, prolonged intense exercise, aging, airway teoblastogenesis. When the bone resorption marker disease, and menopause (from reduced hormone-in- N-Tx is elevated along with these oxidative stress bio- duced respiratory acidosis that causes an increase in se- markers, antioxidants such as vitamin C, a-lipoic acid, rum bicarbonate).97 The phosphate-rich Western diet, and N-acetylcysteine could theoretically reduce all three. high in sulfur-containing animal and grain protein and Vitamin C has been shown to be markedly decreased in low in alkaline fruits and vegetables, results over time in aged osteoporotic women.94 Tobacco smoking, a pro- low-grade metabolic acidosis.98 Metabolic acidosis can oxidant stressor, has been linked to osteoporosis.95 be reduced by promoting renal calcium retention. In a study using oral potassium bicarbonate (60 mEq/day), Additional Metabolic Function Biomarkers Frassetto et al demonstrated a complete neutralization Metabolic function testing can provide a wealth of net acid excretion in healthy older men and women of information relative to detoxification efficiency, ad- by reducing urine calcium losses by just 28 mg/day.99 renal stress, and the presence of intestinal pathogenic It has been known for over 80 years that meta- microbial compounds. Intestinal dysbiosis biomark- bolic acidosis leads to bone loss100 and in vitro research ers are indirect evidence of microbial overgrowth and has illuminated the exact mechanisms for this loss. increased toxic load. Microbial overgrowth can cause Long-term acidosis increases osteoclastic activity,101 re- steatorrhea, a sign of reduced vitamins D and K and duces osteoblastic function,102 increases urine calcium calcium absorption. Overgrowth may also cause gen- loss, reduces IGF-1,103 and increases prostaglandin E2 eralized nutritional deficiency and increases in specific (PGE2), RANKL, and M-CSF104 – all of which in- microbial biomarkers may offer evidence of specific de- crease protein catabolism, muscle wasting,105 and bone ficiencies. For example, elevated levels of the biomarker resorption.106 Mild acidosis also increases activity of ca- tricarballylate, a byproduct of a certain strain of aero- thepsin K, a metallo-protease secreted by osteoclasts for bic bacteria, can lead to reduced magnesium, calcium, bone-matrix resorption.102 Even very small pH changes and zinc levels.88 In this author’s experience, correcting (as little as 0.05) result in a doubling or halving of re- major dysfunctions identified by these tests can lead to sorption-pit formation in cultured osteoclasts.92 PTH parallel improvements in bone-formation markers or release is also affected by acidosis. It has been demon- the reduction in resorption marker N-Tx. strated in dogs that acute metabolic acidosis stimulates PTH secretion and prolongs its half-life, thereby in- Acid-Base Balance: Metabolic Acidosis creasing calcium resorption.107 In a study using growing Bone has three general functions – structural rats, a high phosphate diet, even with adequate calcium support, vital organ protection, and storage for mineral intake, was shown to increase PTH and reduce BMD reserves. This last function is intimately connected to and bone strength.108 the pathophysiology of osteoporosis and, in particular, Hypoxia from increased anaerobic metabolism to the maintenance of blood pH. reduces energy production and contributes to metabolic Arterial blood pH must be maintained at ap- acidosis. The source of hypoxia does not matter; its det- proximately 7.4; even small changes can be life threaten- rimental effects will be the same whether it is produced ing. Acidic hydrogen ions, continuously produced dur- from oxygen debt in the body of a high-intensity, well- ing biological activity, are buffered by the dietary intake trained, endurance athlete or from reduced hematopoi- of alkaline minerals. When the net endogenous pro- etic and oxygen-carrying capability of the fat-infiltrated duction of acid (NEAP) is higher than the dietary base marrow of an 80-year-old patient’s severely osteoporotic load during brief periods, sodium and potassium from bones.93 the metabolically active membrane surrounding bone Page 124 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 13. Alternative Medicine Review Volume 12, Number 2 2007 Review Article Although it is generally agreed that diets high response, increasing Tregs, and reducing interleukin-12 in fruits and vegetables reduce acid load and protect (IL-12) and Th1 dominance, all of which result in a against bone loss,109 it appears more than alkalinity is moderating effect on osteoclastic bone resorption.33 responsible for their protective effects. Muhlbauer et al To maintain normal bone cell function, se- found reduced bone resorption in rats from a diet high rum 25(OH)D level should be considered the func- in alkaline fruits and vegetables may be a reflection of tional indicator for vitamin D status114 and serum levels pharmacologically active compounds rather than the al- maintained between 30 and 80 ng/mL. Vitamin D de- kalinity of the diet and concluded that the acid hypothe- ficiency (<15 ng/mL)113 leads to secondary hyperpara- sis of bone loss may only be applicable to older adults.110 thyroidism and, when severe, can present as severe bone Patients with mild metabolic acidosis often pain, muscle weakness, and increased body sway that have low urine pH (<6.0). Although normal kidneys can lead to falls and hip fractures.115 Improved levels of produce urine with a wide range of pH, serial pH as- vitamin D increase muscle strength and balance and can sessment of first-morning urine averaging <6.0 is a good reduce fracture risk independent of BMD.116,117 1,25- indicator of mild metabolic acidosis and can provide a dihydroxyvitamin D (1,25(OH)2D) is the biologically useful tool for improving patient compliance. In a study active form of vitamin D and is considered a hormone. of the catabolic effects of chronic metabolic acidosis Although reduced serum levels are seen with impaired on muscle protein in postmenopausal women, 60-120 renal function,118 1,25(OH)2D is usually normal even mmol/day potassium bicarbonate resulted in a reduc- when 25(OH)D levels are extremely low. tion in pretreatment levels of metabolic acidosis and the rate of muscle proteolysis.111 In a similar study of post- Vitamin K Status menopausal women, 60-120 mmol/day potassium bi- While vitamin D is important for calcium ab- carbonate resulted in reduced urinary calcium excretion sorption from the gut, vitamin K is needed to reduce and bone resorption and increased bone formation.98 renal calcium loss,119 and a deficiency is associated with In addition to low urine pH, hypercalciuria, reduced BMD and increased fracture risk.120,121 Vitamin low-normal blood bicarbonate, elevated 1,25(OH)2D, K acts as a cofactor in the gamma-carboxylation of glu- low IGF-1, mild hypothyroidism, and mild hypophos- tamic acid residues of many calcium-binding proteins. phatemia may be indicators of low-grade metabolic This post-translational carboxylation is important for acidosis.112 When assessing a patient for mild metabolic normal blood coagulation and bone formation. acidosis, a more global view of the patient is preferable There are three known bone-matrix vitamin to relying solely on urine pH. As a cautionary note, el- K-dependent proteins important for bone formation: evated urine alkalinity of pH >8.0 can be a sign of uri- osteocalcin, matrix Gla protein (MGP), and protein nary tract infection or renal disease. S. Osteocalcin production by osteoblasts is induced by 1,25(OH)2D,122 and vitamin K is responsible for the Vitamin D Status carboxylation activation of osteocalcin that appears to Receptors for vitamin D have been found on be necessary for nucleation of the hydroxyapatite crys- cells in many organ systems throughout the body. In tal. Vitamin K deficiency leads to the under-carboxyl- addition to its role in mineral metabolism and mainte- ation of osteocalcin.123 Oral anticoagulants, which are nance of intracellular calcium levels, it is important for antagonists to vitamin K, have been shown to cause an cell differentiation and proliferation, muscle growth, and under-carboxylation of both MGP and osteocalcin.124 strength. Vitamin D deficiency not only causes bone Low levels of carboxylated osteocalcin or high levels of fragility but has also been linked to increased cancer under-carboxylated osteocalcin (ucOC) carry an in- risk, type 1 diabetes, and heart disease.113 Vitamin D is creased risk for femoral neck fracture.124 MGP is both essential for normal insulin secretion and is thought to a bone-matrix protein and a chondrocyte protein that act as an immunomodulator since vitamin D receptors inhibits calcification. Vitamin K deficiency can reduce (VDRs) are seen on macrophages, dendritic cells, and MGP and lead to excess soft-tissue calcification. Kiel et activated T cells. In the presence of vitamin D, dendritic al identified a correlation between arterial calcification cells mature as more tolerogenic, thus modulating T-cell and osteoporosis.125 Page 125 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 14. Alternative Medicine Review Volume 12, Number 2 2007 Osteoporosis Biomarkers Estrogen is thought to play a part in vitamin case of a ratio >0.2, 24-hour urine calcium should be K metabolism. Serum phylloquinone levels are not lin- obtained (upper limits of 250 mg/day for females and early related to the levels of carboxylated osteocalcin 300 mg/day for males). A high urine volume is often and estrogen may be an influencing factor in this dis- seen in hypercalciuric patients because urine calcium crepancy.126 Yasui et al demonstrated serum ucOC has stimulates calcium receptors in the renal collecting ducts a negative correlation with estradiol and a positive cor- and inhibits antidiuretic hormone. These patients tend relation with FSH levels in perimenopausal women.127 to have frequent clear urination of a pH< 6.0. If the Therefore, even with adequate serum phylloquinone, uCa/Cr is <0.1, ensure that the patient has adequate reduced levels of estrogen may impair carboxylation of calcium intake and if the ratio remains <0.1, malabsorp- osteocalcin and limit bone mineralization. tion should be ruled out. The uCa/Cr ratio should only The body stores minimal vitamin K and, al- be used as a screening test for hypercalciuria and not though severe deficiency leading to impaired blood as a diagnostic screen for osteoporosis.136 Hypocalciuria clotting time is uncommon, mild levels of vitamin K is seen in celiac patients and can be confirmed with a deficiency are common. Although prothrombin time serum anti-tissue transglutaminase assay. (PT) is a test for deficiencies in vitamin K-dependent Hypercalciuria is a common contributing fac- clotting factors, it is not a sensitive biomarker for mild tor in osteoporosis and therefore, in addition to bisphos- vitamin K deficiencies. Although ucOC is a very sen- phonate therapy, thiazide diuretics are often prescribed. sitive marker for vitamin K, especially when used as a Although thiazides reduce urine calcium excretion and ratio in proportion to osteocalcin levels, it has not been lower serum PTH levels, they do not affect gastroin- approved for clinical use. testinal calcium absorption. Studies are mixed as to the Although serum phylloquinone is a clinically effectiveness of thiazide diuretics for the treatment of available test for vitamin K status, it is of limited use osteoporosis. Although some studies show an increase because it is influenced by estrogen, triglycerides,128 in BMD with thiazide use,137,138 others fail to show a and recent dietary vitamin K intake. In addition, serum statistically significant difference in reduced fracture phylloquinone levels do not determine the status of vi- rate between thiazide users and nonusers.139,140 tamin K-dependent bone-matrix protein carboxylation. Because thiazide diuretics have been linked to Therefore, currently there are no clinically available and reduced glucose tolerance, the possibility for increased reliable tests for assessing vitamin K or ucOC status. falls,141 and a reduced hypocalciuric effect over time, it Martini et al showed a significant reduction of makes therapeutic sense to approach hypercalciuria nu- serum N-Tx (an indicator of bone resorption) in post- tritionally with a trial of supplemental vitamin K and menopausal women treated with 450 mcg phylloqui- potassium. Vitamin K is not only important for car- none daily.129 Very high doses (45 mg/day) of vitamin boxylation of osteocalcin but also for calcium reabsorp- K2 have been used to treat postmenopausal osteoporo- tion.142 Potassium (citrate and bicarbonate) has been sis in Japan with no reported adverse effects.130-132 shown to reduce urine calcium loss98,143 and improve BMD.144,145 Counseling the patient to increase dietary Urine Calcium Loss intake of fruits and vegetables, while restricting acidic Excess urine calcium loss is a common find- foods and high-phosphoric-acid cola drinks (shown to ing in osteoporosis (and kidney stones). Hypercalciuria reduce BMD),146 will also reduce urine calcium losses. causes renal-magnesium wasting133 and may be caused by excess calcium intake, increased intestinal calcium absorption, hyperparathyroidism, or a benign renal cal- cium leak. Although influenced by sodium intake and urine volume,134 urine calcium/creatinine ratio (uCa/ Cr) can be used as a general screening tool for calcium levels in the urine135 – normal ratio is 0.1-0.2. In the Page 126 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 15. Alternative Medicine Review Volume 12, Number 2 2007 Review Article Serum Calcium, Phosphorus, and Hypophosphatemia Parathyroid Hormone 1,25(OH)2D increases intestinal absorption Hypercalcemia of phosphorus and, in vitamin D deficiency, serum Hypercalcemia is the hallmark of hyperpara- and urine phosphorus levels may be reduced,112 which thyroidism (malignancy is the cause of hypercalcemia can lead to osteomalacia. If serum phosphorus is low in approximately 50 percent of hospitalized patients),147 from a nutrient-deficient diet or intestinal malabsorp- and when calcium levels are >10.5 mg/dL, serum PTH tion, 1,25(OH)2D production increases and improves will confirm the diagnosis. In this hypercalcemic con- intestinal absorption, and PTH will decrease thereby dition, PTH stimulates 1-alpha hydroxylase in the reducing renal losses of phosphorus. Because PTH in- kidney, elevating 1,25(OH)2D and increasing urine creases renal clearance of phosphorus, hypophosphate- calcium losses. mia may be seen in hyperparathyroidism. Hypophos- phatemia can therefore be seen with either reduced 1,25(OH)2D production in the hypocalcemic patient Hypocalcemia with renal disease or in the hypercalcemic primary hy- Hypocalcemia may be from malabsorption, perparathyroid patient.149 Hypophosphatemia is also magnesium deficiency,148 or reduced levels of PTH. present in other disease processes and several genetic Even borderline-low serum calcium signals a possible disorders. magnesium deficiency. Commonly deficient, magne- sium is often low due to diabetes, alcoholism, malab- sorption, steatorrhea, poor diet, or genetically-based re- Hypoparathyroidism duced intestinal uptake. Magnesium is an intracellular Functional hypoparathyroidism is character- cation, and its depletion reduces renal conservation of ized by low 1,25(OH)2D, hypocalcemia, and low-to- potassium vital for cellular water balance and pH ho- normal PTH, and appears to be associated with mag- meostasis. Because only one percent of magnesium is nesium deficiency.150 Typically, low vitamin D levels lead found in the extracellular fluid, serum magnesium test- to an elevation of PTH to maintain calcium homeo- ing does not accurately reflect overall levels.133 stasis; however, a failure of PTH to increase is termed functional hypoparathyroidism. Although PTH pro- duction depends on at least one magnesium-dependent Hyperphosphatemia enzyme,151 magnesium’s full role in PTH production is Phosphorus is one of the most abundant min- still unclear. PTH secretion may be dependent on the erals in the body and along with calcium constitutes magnesium-dependent enzymes adenylate cyclase or a major portion of the hydroxyapatite crystal in bone guanine nucleotide.152 In functional hypoparathyroid- mineralization. Phosphorus is found in most foods and ism, magnesium supplementation will increase PTH therefore dietary intake is usually sufficient for bone levels to normal, even in the face of vitamin D defi- health, if not excessive in the Western culture. Phospho- ciency, underscoring the importance of checking both rus and calcium levels are maintained through PTH, 1,25(OH)2D and 25(OH)D. vitamin D, and changes in renal tubular reabsorption rates. High dietary intake of phosphorus inhibits re- Hyperparathyroidism nal reabsorption, thus maintaining normal serum levels. Serum IL-6 levels, known to increase with But in severe renal failure or in the osteoporotic patient estrogen deficiency, are elevated with both symptom- with chronic metabolic acidosis, high dietary intake of atic and mild asymptomatic primary hyperparathyroid- phosphorus can lead to hyperphosphatemia. In these ism.153 With IL-6 testing not easily available, elevated situations the elevation in serum phosphorus leads to PTH can be reduced with vitamin D and calcium reduced 1,25(OH)2D production, limiting intestinal supplementation, but also by reducing IL-6-related calcium absorption and resulting in hypocalcemia and chronic inflammation and improving acid/base balance. secondary hyperparathyroidism.149 Hyperphosphate- Depending on estrogen levels, the use of exogenous es- mia is also observed in several genetic disorders and trogen replacement may also be considered. may be present in patients using bisphosphonates.149 Page 127 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 16. Alternative Medicine Review Volume 12, Number 2 2007 Osteoporosis Biomarkers Secondary hyperparathyroidism is seen with risk.157 In a study of 959 healthy postmenopausal wom- aging and the loss of the calcitrophic effects of estrogen. en, those with low-normal TSH levels (0.5-1.1 µU/ Mild increases in PTH are often observed in vitamin mL) had lower BMD of the lumbar spine and femoral D deficiency, hypercalciuria, or insufficient intake or re- neck than those with high-normal levels (2.8-5.0 µU/ duced absorption of calcium. mL).158 Anti-Tissue Transglutaminase and Celiac Hypothyroidism Disease Reduced thyroid function has been linked to Celiac disease (CD) is caused by an autoim- low femoral neck BMD,159 decreased IGF-1 produc- mune reaction to the protein gluten that results in in- tion,160,161 and increased fracture risk.162 Suboptimal flammation and villous atrophy of the small-intestinal zinc levels in patients with hypothyroidism may also mucosa. Common symptoms include diarrhea, flatu- contribute to bone loss. Zinc is important for energy lence, steatorrhea, musculoskeletal complaints, abdomi- metabolism and also for bone growth and production of nal distention, and dermatitis herpetiformis;154 however, thyroid hormones. Zinc deficiency retards bone growth in its atypical form there may be no overt symptoms. As- and can be a contributing factor in the development of sociated malabsorption of iron, folic acid, calcium, zinc, osteoporosis.163 The enzyme 1,5′-deiodinase that con- and the fat-soluble vitamins A, D, E, and K can lead to verts thyroxine (T4) to T3 is zinc dependent. Baltaci anemia and bone loss, often present in celiac patients. et al demonstrated in rats that T4, T3, and TSH levels Serological tests aid in the diagnosis of gluten decrease with zinc deficiency.164 Zinc deficiency165 and sensitivity and should be considered in a patient with reduced thyroid function are common in high-inten- reduced BMD, gastrointestinal symptoms, unidentified sity athletes. Chronic metabolic acidosis has also been neuro-musculoskeletal complaints, or if the patient has linked to reduced thyroid function.166 a first-degree relative with CD. Serum tissue transglu- taminase antibody (tTGA) is a highly sensitive test for Homocysteine identifying both classical and atypical CD.155 Further Homocysteine (HCY), a metabolite of the testing for CD includes anti-gliadin antibodies and anti- amino acid L-methionine, interferes with collagen endomysial antibodies. If necessary, histological confir- cross-linking and is related to increased hip-fracture mation of CD is made through small bowel biopsy or rate,167 independent of BMD.168 Osteoporosis is a com- a gliadin rectal challenge. Treatment of CD is through mon symptom of homocysteinuria, a rare autosomal strict avoidance of gluten protein found in wheat, barley, recessive disease caused by mutation of the gene for rye, and oats. methylenetetrahydrofolate reductase (MTHFR). The enzyme MTHFR is necessary for HCY metabolism. Thyroid Effects on Bone Milder elevations of HCY occur with a T homozygous polymorphism for MTHFR and may be linked to an Hyperthyroidism increase in fracture risk. This common polymorphism Thyrotoxicosis can cause hypercalcemia with creates a less-active enzyme, causing serum HCY to in- secondary suppression of PTH and increased urine cal- crease and was shown in a study with postmenopausal cium losses, leading to bone loss. Elevated thyroid hor- Japanese women to be associated with lower BMD.169 mone increases bone remodeling by directly stimulating Serum HCY levels >15 µmol/L are associated both osteoblast and osteoclast activity and increasing with increased bone turnover markers (osteocalcin and production of IGF-1. While triiodothyronine (T3) in- Dpd) and increased fracture risk.170 Gjesdal et al ob- creases bone resorption, thyroid-stimulating hormone served a statistically significant 2.5-fold increase in frac- (TSH) from the anterior pituitary gland directly sup- ture risk with HCY levels >15 µmol/L. The study dem- presses osteoclastic resorption.156 Serum TSH of <0.5 onstrated a positive linear relationship between HCY µU/mL appears to inhibit the formation, function, levels and fracture risk (p for trend).171 In a review, Saito and survival of osteoblasts, independent of T3 and T4, and is associated with bone loss and increased fracture Page 128 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 17. Alternative Medicine Review Volume 12, Number 2 2007 Review Article describes that even mild hyperhomocysteinemia reduces 182 and have been shown to inhibit IGF-1 secretion, bone quality and increases bone fragility.172 HCY levels which leads to sarcopenia and bone loss. A decline in increase with age and, because 5-15 percent of Cauca- IGF-1 is seen with waning estrogen in postmenopausal sian women in North America are T homozygous for women183 and higher IGF-1 levels are associated with MTHFR, serum testing for homocysteine is important greater BMD in older women.184 Although reductions when assessing a patient with bone loss. in IGF-1, insulin, and growth hormone are associated In addition to increased bone loss and fracture with longevity,185 low serum IGF-1 in the presence of risk,168 elevated HCY has been linked to chronic inflam- bone fragility strongly indicates the need for a protein- mation. In cultured cells, HCY has also been shown to enriched, anabolic-promoting diet and a reduction in increase apoptosis of osteoblasts by increasing intra- catabolic influences such as hyperglycemia. Although cellular ROS.173 Homocysteine is also correlated with hyperinsulinemia is correlated with increased IGF-1 increased lipoprotein oxidation and the formation of levels, in a study by Martin et al, IGF-1 was only weakly PPARγ ligands, associated with reduced BMD in mice. positively correlated to insulin resistance.186 Vitamins B6 and B12, folate, and riboflavin are Dietary protein supplementation187 with necessary cofactors for the metabolism of HCY.174 Be- whey and milk basic protein (whey’s basic protein frac- cause a defect in MTHFR may cause a deficiency of the tion),188,189 colostrum,190 and the amino acids L-arginine, active form of folate, 5-methyltetrahydrofolate would glutamine, ornithine, lysine, and glycine raise serum be the form of choice for managing homocysteinemia. IGF-1 and may reduce fractures. Milk basic protein Testing of urine organic acid helps identify vitamin B has been shown to reduce bone resorption and increase insufficiencies. Elevated methylmalonate, a metabolic bone formation in women191 and men.192 Supplemen- intermediate of the amino acid valine, indicates the need tation with DHEA and zinc, improving sleep patterns, for vitamin B12.88 and engaging in moderate exercise can help increase The conditionally essential amino acid taurine IGF-1 levels.193,194 Osteoporotic patients are known to is an end-product of methionine metabolism and oral have lower zinc levels,195 and both zinc and copper are supplementation can help counteract the negative ac- recommended163 for reducing bone loss in patients with tions of elevated HCY levels.175 Taurine and N-acetyl- osteoporosis.196,197 In studies with rodents, zinc and cysteine are also known to inhibit hydrogen peroxide IGF-1 stimulated DNA synthesis for bone growth,198 and superoxide anion secretion176 and to help increase increased osteoblastic bone formation, and reduced os- superoxide dismutase levels,177 all of which are impor- teoclastic resorption.199 tant for reducing the catabolic state of chronic degen- Abnormally low levels of IGF-1 may indicate erative disease. a catabolic physiology. However, because genetics sub- stantially influence IGF-1, low serum levels may be Insulin-like Growth Factor-1 found even with normal endocrine function. For this The anabolic actions of growth hormone are, reason, and the fact that a majority of IGF-1 in bone is to a great extent, due to the effects of IGF-1 from the derived from osteoblasts and not from the circulation,200 liver. IGF-1 is a potent anabolic agent estimated to di- it is important to look at a patient’s overall presentation rectly influence approximately one-third of the factors and take into consideration all the biomarkers used in involved in skeletal growth, including calcium and phos- the evaluation. For example, when retesting for efficacy phorus metabolism.178 Because IGF-1 is homologous to of treatment, improvements in one or two biomarkers human pro-insulin, it is affected by glucose metabolism (e.g., reduction in N-Tx and urine calcium losses) may and insulin levels. indicate improved catabolic physiology even with no im- Receptors for IGF-1 are found on osteoblasts, provement in IGF-1. Testing of IGF-1 can be through osteoclasts, and osteocytes,179 and even small changes serum or saliva (active, free form). in IGF-1 levels in mice have been shown to affect bone mass.178 Oxidative stress and IL-6 increase with aging180- Page 129 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 18. Alternative Medicine Review Volume 12, Number 2 2007 Osteoporosis Biomarkers C-Reactive Protein risk in older adults has been linked to mild increases C-reactive protein (CRP) is an abnormal gly- in endogenous cortisol levels.217 And even the subtle coprotein produced in the liver in response to inflam- stress of dietary restraint in normal-weight females in- mation. Although several studies have failed to demon- creases urine and salivary cortisol concentrations218,219 strate a direct association between serum CRP and bone and has been shown to reduce bone mineral content. In density,201-203 others show that higher CRP levels are a study of 65 healthy women with high cognitive eat- associated with reduced BMD.204,205 Pasco et al found ing restraint scores, reduced levels of serum osteocalcin a 23-percent increase in fracture risk, independent of indicated lower bone turnover (although BMD changes BMD, with each standard deviation increase in high- were not apparent).220 sensitivity CRP (hs-CRP).206 The inflammatory cyto- Mild chronic stress causes bone loss in mice kine IL-6 has been shown to stimulate the production via activation of the sympathetic nervous system (SNS) of CRP.182 In addition to the IL-6 involvement in osteo- and the hypothalamic-pituitary-adrenal (HPA) axis.221 clastogenesis and bone loss, it is also catabolic to muscle Stimulation of the SNS increases RANKL in osteo- tissue by reducing IGF-1 levels207,208 and contributes to blasts and progenitor cells,222 which increases osteoclas- the sarcopenic phenotype commonly seen in the osteo- tic activity. Stress and chronic activation of the HPA porotic patient. axis raise serum cortisol and reduce levels of another ad- Because clinical testing for proinflammatory renal steroid, DHEA. The effects of chronically elevated cytokines is not commonly available, testing for hs- cortisol or reduced DHEA can be similar to those of CRP can reflect increased proinflammatory cytokine exogenous glucocorticoids – a decrease in IGF-1 with levels. Lifestyle changes and dietary supplementa- a concomitant increase in bone marrow infiltration by tion such as a-lipoic acid, N-acetylcysteine, tau- adipocytes.215 rine,209 and curcumin210,211 to relieve oxidative stress Cortisol can be measured in the blood, urine may help reduce hs-CRP levels. Omega-3 fatty acids (24-hour urine sample), or saliva. Cortisol levels have DHA and EPA are known to reduce proinflamma- a circadian rhythm and normally peak in the morning tory cytokines, and the omega-6 α-linolenic acid has (0700 hours) and are at their lowest in the late evening been shown to reduce CRP.212 CRP concentrations (2300 hours). With multiple saliva samples a 24-hour were reduced in smokers (or individuals passively cortisol circadian rhythm can be determined.223 Sali- exposed to cigarette smoke) with 515 mg/day sup- vary assays are useful in the identification of adrenal plemental vitamin C.213 insufficiency224 and late-night salivary cortisol measure- ment is a useful screen for Cushing’s Syndrome.225 El- Cortisol, Neurotransmitters, and DHEA evated night-time salivary cortisol has been linked to Both cortisol elevation and reduced levels of reduced lumbar spine BMD in men and women (not DHEA are linked to osteoporosis. Cortisol is released on HRT).226 In a study to compare the accuracy of two from the adrenal cortex when stimulated by adreno- different methods – radioimmunoassay (RIA) and en- corticotropic hormone (ACTH) from the pituitary zyme immunoassay (EIA) – for measuring salivary cor- gland in response to stress. Prolonged exposure to cor- tisol, RIA was the more accurate method, while EIA tisol is associated with adipocyte bone marrow infiltra- overestimated cortisol concentration.227 This under- tion, reduced BMD, and increased fracture risk.214,215 scores the importance of comparing values from similar In a study with sleep-deprived women, Specker et al methods when doing serial testing. demonstrated that elevated cortisol levels were associ- DHEA is metabolized to androstenedione, ated with reduced volumetric BMD.216 Volumetric den- which is the precursor to androgens and estrogen. sity, a measurement that includes bone size, is obtained DHEA levels are inversely correlated with N-Tx in an- through quantitative computer tomography and desig- orexic girls228 and oral supplementation can reduce re- nated in g/cm3, compared to projected areal density of sorption markers and increase bone formation markers DXA, which is designated in g/cm2. Increased fracture Page 130 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 19. Alternative Medicine Review Volume 12, Number 2 2007 Review Article in anorexic women.229 Kahn et al, however, did not find low serum IGF-1, and/or loss of estrogen can lead to a reduction in bone turnover markers in men supple- an increase in PPARγ production and adipocyte devel- mented with 90 mg/day oral DHEA for six months.230 opment at the expense of osteoblastogenesis. Both an Oral DHEA supplementation also increases estradiol increase in bone marrow adiposity and a suppression levels in men and postmenopausal women231 and can in- of osteoblastic activity are seen with the activation of crease osteocalcin and IGF-1.232 When levels of DHEA/ the adipocyte-specific transcription factor PPARγ2 in DHEA-S are abnormally low, oral supplementation of aging mice.239 Magnetic resonance imaging reveals that 50-100 mg/day can increase BMD.229 Moderate-to-in- postmenopausal women have twice the level of bone tense exercise helps increase endogenous DHEA. marrow fat as premenopausal women, and the lower DHEA and DHEA-S levels may be assessed the bone density the greater the saturated-fat con- through serum233 or saliva. Salivary assays measure tent.240 Parhami has hypothesized that accumulation of unbound, free-circulating hormones. Evaluation us- bone marrow fat in an environment of increased oxida- ing cotton-absorbing, sample-collecting materials have tive stress increases lipoprotein oxidation. With oxida- been shown to artificially elevate DHEA levels.234 tion, ligands for the expression of PPARγ increase and Urine organic acids are helpful in defining mMSC differentiation is diverted from osteoblasts to and monitoring stress and therapeutic efficacy in the adipocytes. This oxidation-driven diversion creates an fracture-risk patient. Urinary breakdown products of increase in RANKL-dependent osteoclastic activity.237 adrenal medullary neurotransmitters can help assess a Therefore, hyperlipidemia and markers for free radical patient’s stress level and adrenal health. These break- oxidative stress (such as urine lipid peroxides) may be down products include vanillylmandelic acid (VNA; risk markers relevant to increased bone fragility. Many end-product of epinephrine and norepinephrine me- nutrients and plant extracts can decrease lipid peroxida- tabolism), homovanillate acid (HVA; metabolite of tion. For example, lycopene has been shown to decrease dopamine), and 5-hydroxyindoleacetic acid (5-HIAA; both lipid peroxidation241,242 and the bone-resorption metabolite of serotonin). marker N-Tx in postmenopausal women.243 Low-Density and High-Density Glucose Lipoproteins Abnormal blood glucose control is also a risk The biomarkers, low-density lipoprotein (LDL) factor for bone loss. Reduced bone mass and increased and high-density lipoprotein (HDL), most relevant to fracture rate are common in type 1 diabetes and are cardiovascular disease (CVD), may also be indicators of linked to PPARγ and preferential adipogenesis over reduced bone quality and increased fracture risk. HDL, osteoblast-cell development.244 Diabetic mice demon- long understood as protective in CVD, has recently strate reduced IGF-1 levels, increased bone marrow been identified as a possible regulator of osteoblast cell adipocyte-infiltration that leads to reduced RBCs, and differentiation.235,236 Parhami et al demonstrated that reduced osteoblast formation and maturation (reflected products of lipid and lipoprotein oxidation from a high- by a reduction in osteocalcin).244 Diabetic patients have fat diet are the source of PPARγ-activating ligands and reduced late-stage differentiation of osteoblasts and a can lead to a loss of bone density in mice.237 It is the decrease in osteoblast function.245 commonality of osteoblast and adipocyte stem cells that Advanced glycated end products (AGEs) have links osteoporosis and obesity (Figure 2),238 two of the been linked to abnormal development of osteoblasts most common conditions in the United States, and an and are thought to enhance bone resorption and induce over-expression of PPARγ interferes with normal dif- apoptosis of mMSCs.246 Enzymatic cross-linkage of col- ferentiation of their common precursor cell. lagen fibers gives strength to bone, but AGE-induced, Bone marrow mesenchymal stem cells non-enzymatic collagen cross-linkage leads to increased (mMSC) differentiate into either osteoblasts or adi- fracture risk.247 AGE accumulation from increased oxi- pocytes, depending on their environment. Elevated tri- dative stress occurs more readily in highly mineralized glycerides, reduced control of blood glucose, abnormally bone,247 such as that which occurs in long-term bisphos- phonate use, and may contribute to increased fracture Page 131 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 20. Alternative Medicine Review Volume 12, Number 2 2007 Osteoporosis Biomarkers risk. For this reason, glucose control of the patient on determinant of femoral bone loss in women within bisphosphonate therapy is essential. the first decade after menopause.253 Proinflammatory Thiazolidinediones (Avandia; Actos), artificial cytokines increase T-cell activation and the release of PPARγ agonists used for the treatment of type 2 dia- RANKL, which promotes NFkB, the key transcription betes, inhibit osteoblastogenesis and have been shown factor in osteoclastogenesis. The rise in proinflamma- to reduce BMD in mice.248 Therefore, these medica- tory cytokines from reduced estrogen also stimulates tions should be avoided if possible in patients with low mMSC production of IL-7, which has been shown to BMD. suppress bone formation and increase RANKL stimu- lation of osteoclasts in mice.254 Sex Hormones As mentioned previously, oxidative stress plays Estrogen a major role in chronic degenerative diseases includ- Since publication of the findings of the Wom- ing osteoporosis. Estrogen suppresses ROS, which are en’s Health Initiative (WHI) program, the role of hor- known to stimulate osteoclast activity255 through the mone replacement therapy (HRT) in the management activation of NFkB; with a loss of estrogen, ROS in- of osteoporosis has been questioned, even in light of a crease. Antioxidant supplementation to down-regulate 33-percent reduction in hip-fracture rate.249 Although IL-6 gene expression and TNF-a-induced NFkB is HRT (estrogen plus progestin) slows bone loss, in- recommended, especially in women with low estrogen creases bone mineral density, and reduces fracture levels.255 It has been shown in mice that NAC protects rate,250 the risks of hormone replacement may outweigh against bone loss, possibly through the reduction of the benefits. Although HRT is still used by many phy- ROS.44 The use of a-lipoic acid and NAC have been sicians, there are concerns that it should no longer be shown to reduce ROS-mediated apoptosis of cultured the first choice in treatment for osteoporosis.25 The use human stromal cells (the precursors of osteoblasts).256 of bioidentical hormones, thought to be safer than con- Estrogen improves oral tolerance by suppress- ventional synthetic hormones due to their differences ing the release of TGF-β by dendritic cells and macro- in metabolism,251 have become more popular since the phages, which then limits their antigen presentation.257 WHI. However, as yet, there have been no large-scale With modulation of antigen presentation, RANKL and trials to assess their efficacy or risk. TNF-a production from T-cell activation is reduced. Estrogen is the major hormone regulator of When estrogen is lost dendritic-cell-antigen presenta- bone remodeling and is important for men as well as tion and T-cell activation increases. Because dendritic women. Estrogen’s role in maintaining bone health is cells are activated through redox signaling, the rise in far reaching – from maintaining calcium homeostasis ROS associated with reduced estrogen in osteoporotic by stimulating the release of calcitonin and activating patients could potentially be offset by the use of probi- 1,25(OH)2D receptors in the gut to its function within otics and antioxidants when appropriate. the osteo-endocrine-immunological axis. Estrogen levels fluctuate during the menstrual Estrogen limits bone loss through its effects on cycle and are stable after menopause. A substantial loss osteoblast and osteoclast activity. Estrogen-receptor ac- of bone occurs when endogenous serum estrogen falls tivation of osteoblasts stimulates release of the growth below a critical level in women (approximately 10 pg/ factors TGF-β and IGF-1, and OPG. This in turn lim- mL).258 By understanding estrogen’s connection with its M-CSF and RANKL, which reduces osteoclasto- the immune system as it relates to bone remodeling, the genesis and increases osteoclast apoptosis. nutritionally-oriented clinician can guide patients in Reduction in estrogen leads to increased os- making choices with regard to hormone replacement to teoclastic activity from the reduced hormonal control reduce bone loss. over proinflammatory cytokines, IL-1, IL-6, and TNF- a (which increase when there is a loss of estrogen).252 Elevated serum IL-6 levels are considered the strongest Page 132 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 21. Alternative Medicine Review Volume 12, Number 2 2007 Review Article Follicle Stimulating Hormone proinflammatory cytokine marker soluble IL-6 recep- High serum follicle stimulating hormone tor secondary to reduced sex steroid levels.264 This is an (FSH) >40 mIU/mL in perimenopausal women is a indication that androgens may play a role in both the reflection of low estrogen. The effect of FSH on BMD inflammatory changes and increased bone loss related appears, however, to be independent of estrogen, and a to aging. gradual rise in the follicular phase FSH to >70 mIU/ Although hypogonadal men demonstrate mL is correlated with reduced BMD.259 FSH receptors reduced BMD,265 the relationship of testosterone to are found on osteoclasts and, as the hormone increases, fracture risk has remained unclear. In a recent study, it heightens osteoclastic activity and stimulates TNF-a Mellstrom et al showed low-normal levels of serum free release from macrophages (which is also osteoclasto- testosterone were an independent predictor of BMD genic). Starting premenopause, the use of serial serum and increase in fractures.266 Lorentzon et al showed the FSH testing may provide an early indication of acceler- effects of sex hormone-binding globulin may be inde- ated bone loss. pendent of estrogen and testosterone and that its effects on bone may be age dependent.267 In another study of Progesterone 609 men over the age of 60, low serum testosterone and Although amenorrhea and oligomenorrhea are high SHBG levels were associated with increased risk obvious signs of hormonal dysfunction, anovulatory of osteoporotic fractures independent of BMD.268 El- and short-luteal-phase cycles may not be as evident; all evated SHBG in young men may be beneficial for im- scenarios may be associated with reduced BMD.260 Ac- proved bone mass, whereas in elderly men it appears to tivation of the HPA axis, even in mild chronic stress, be a negative predictor of BMD.267 reduces gonadotropin-releasing hormone (GnRH) and Testosterone replacement therapy in men with could result in reduced hormone levels and subclinical severe subnormal serum testosterone levels has been ovulatory disturbances. These abnormal (yet normal shown to reduce bone resorption and reverse deterio- length) cycles can be detected through blood or salivary ration of trabecular architecture.269 Serum testoster- progesterone measurements. For example, suppressed one can be measured as free testosterone or bound to progesterone during the second half of the cycle would SHBG; only free testosterone can be measured through indicate an anovulatory cycle. A short luteal phase saliva. would be indicated if progesterone elevation lasted less than 10 days.218 Effect of Exercise on Bone Health Topical progesterone creams made from di- Exercise has an important influence on bone osgenin, extracted from Mexican yams, are frequently health and is essential for reducing fracture risk. Exer- used for osteoporosis, but their ability to increase BMD cise in adolescence and into adulthood increases BMD remains controversial. Much of the attention for the and preserves bone health.270,271 use of progesterone has been due to the conclusions of In addition to improving mitochondrial bio- Lee on the efficacy of transdermal progesterone cream energetics, exercise also increases the anti-inflamma- to increase BMD in postmenopausal women.261 In a tory cytokine IL-10 and the inflammatory modulator study by Leonetti et al there was no increase in BMD in IL-1 receptor antagonist molecule.272,273 Encouraging menopausal women treated daily for one year with 20 exercise in patients increases IGF-1193 and is vital for mg progesterone cream.262 increasing muscle strength and coordination. Exercise reduces the risk for falls, the number-one risk factor for Testosterone and Sex Hormone-Binding fracture.274,275 Globulin Although exercise has many benefits for bone Although reduced estradiol has a clear asso- and general health, chronic, high-intensity, excessive ex- ciation with increased fracture incidence,263 the effects ercise subjects the athlete to hypoxia, metabolic acido- of low testosterone on bone in men and women have sis, excessive oxidative stress, and elevated levels of pro- been less definitive. As men age, there is a rise in the inflammatory cytokines;276 instead of being anabolic, exercise becomes catabolic when taken to excess. Page 133 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007
  • 22. Alternative Medicine Review Volume 12, Number 2 2007 Osteoporosis Biomarkers Athletes participating in an ultra-distance run- concerns, including a possible increase in fracture rate ning race experienced an 8,000-fold elevation in IL-6 after long-term use.291 However, a multicenter study of levels,277 and in another study of male long-distance 994 postmenopausal women concluded there was no runners, bone turnover markers were increased and increase in fracture rate after 10 years of alendronate bone mass was reduced compared to controls.278 Eleva- therapy.292 ted levels of IL-6 result in increased lipid oxidation and Most recently, it has been demonstrated that PPARγ production; T-cell activation with increased bisphosphonates can cause severe suppression of bone RANKL production can also result.236 The sleepiness turnover293 and possibly lead to osteonecrosis of the and fatigue of “sickness syndrome” produced by IL-6 jaw (ONJ). Pamidronate (Aredia®) and zoledronic acid during severe exercise helps prevent athletes from in- (Zometa®), both intravenous bisphosphonates for can- flicting excess tissue damage on their bodies. cer chemotherapy,294 and the oral bisphosphonates alen- dronate and risedronate for the treatment of osteoporo- The Need for a Different Approach to sis,295 have all been linked to ONJ. Bone Health Hormone replacement therapy remained the Conclusion first choice in osteoporosis prevention and treatment When assessing treatment options for patients for postmenopausal women until July 9, 2002, when the with increased bone fragility, fracture risk needs to be Women’s Health Initiative study250 was abruptly halted. weighed against the potential for iatrogenic effects of The study was discontinued with the early observation bisphosphonates. Because bisphosphonates have not that conjugated equine estrogen plus synthetic proges- proven cost-effective in treating women with femoral tin (medroxyprogesterone acetate) increased the risk of neck T scores better than -2.5 with no history of frac- breast cancer, cardiovascular disease, stroke, and venous ture,296 the use of biomarkers to monitor bone health thromboembolism.279 Although the study also showed and the use of nutritional therapy to prevent or treat a decreased risk of hip fracture with the use of HRT, osteoporosis seems prudent. But despite mounting sci- the risks outweighed the benefits.248 entific evidence pointing to the efficacy of nutritional In the last decade the use of bisphosphonate interventions for bone preservation, conventional phy- therapy for osteoporosis has gradually increased. And, sicians have been slow to embrace such interventions. although it has been well documented that bisphos- This was demonstrated in a study that found, even phonates limit osteoclastic bone resorption,280 increase though hypovitaminosis D is common among physi- BMD, and reduce fractures,281-283 there have been safety cians, they still do not check serum 25(OH)D levels in concerns. patients.297 Bisphosphonates work by reducing resorption Biomarker testing allows detection of metabol- which, when excessive or in the absence of equivalent ic change long before alterations in BMD, underscoring bone formation, leads to bone loss. But osteoclastic re- the need to refocus attention away from reliance solely sorption is essential for bone health, and over-suppres- on BMD testing. A comprehensive approach would em- sion may lead to increased accumulation of microdam- ploy biomarkers to assess risk and identify underlying age,284-286 impaired mineralization,287 reduced toughness, disease mechanisms, including inflammation, oxidative increased brittleness,285,288 and a general reduction in the stress, hormone imbalances, nutrient deficiencies, and biomechanical competence of bone.289 malabsorption. Once the risk factors have been iden- One of the first bisphosphonates used for the tified, a comprehensive, individualized plan, including treatment of osteoporosis was etidronate (Didronel®), diet, exercise, and targeted nutrients, can create a meta- which suppressed bone turnover but, when used in bolic environment conducive to balanced remodeling higher doses, resulted in osteomalacia by impairing os- and healthy bone. teoid mineralization.290 Current bisphosphonates, such as alendronate (Fosamax®) and risedronate (Actonel®), for the treatment of osteoporosis have also raised safety Page 134 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007