Muscle, Bone and Vitamin D: Are There Connections? EFF-ASBMR Fellows Forum September 15, 2016

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1 Muscle, Bone and Vitamin D: Are There Connections? EFF-ASBMR Fellows Forum September 15, 2016 Neil Binkley, M.D. University of Wisconsin School of Medicine and Public Health Research support Amgen Eli Lilly GE Healthcare Merck Opko Ireland Advisory boards Amgen Astellas Bristol-Myers Squibb Eli Lilly Merck Nestle Disclosures Disclosures (2) Much of This is My Opinion Noted by Orange Text Think, Don t Just Accept Dogma/Status Quo Only doubt is certain and disbelief worth believing. Without this courage there can be no learning. Believe nothing. Anonymous Summary Bone and muscle are interconnected in the pathophysiology leading to what are currently called osteoporosis-related fractures We should be thinking not just about osteoporosis and not just about sarcopenia, but rather about dysmobility syndrome which has adverse outcomes of falls & fractures The vitamin D world is in chaos Vitamin D DEFICIENCY leads to weak bone and muscle, but it is unknown what role(s), if any, vitamin D INADEQUACY plays in bone health and muscle function What is Osteoporosis? A systemic skeletal disease characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Consensus Development Conference: Diagnosis, Prophylaxis, and Treatment of Osteoporosis. Am J Med. 1991; 90:107-

2 Why Do You Treat Osteoporosis? Fracture is What s Important On My Watch, We Have Failed to Prevent Fractures..have we, as a community of experts, failed to communicate clearly to the public the benefits versus the risks of osteoporosis therapy? Have we also failed to adequately educate the public about the devastating consequences of osteoporosis the loss of mobility and markedly reduced quality of life following vertebral fracture and the likely death-spiral following hip fracture? If we fail, all our efforts for some of us, our life s work will have been for naught. Although we could individually bemoan this loss, that would be self-serving. The only issue that really matters is that we would have failed our patients, and that is something we cannot allow to happen. Khosla and Shane, J Bone Min Res, 2016 DOI: /jbmr.2888 ~80% of Those Who Break Their Hip Receive NO Treatment to Reduce Future Fracture Risk (and it s getting worse) 40% 21% It is scandalous that this treatment gap is so marked in the case of hip fracture. It is now time for us all to accept responsibility for our failures and work cohesively to improve. Kanis, et. al, JBMR, Sept 2014 pp Solomon, et al., J Bone Min Res, 2014 DOI: /jbmr.2202 United HealthCare data; Proportion of patients in each quarter ( ) who received a BP or other osteoporosis med after hip fx n = 22,000+ Average age 72 68% female these results highlight the need to weigh benefits versus harms of bisphosphonates and to improve the communication of drug safety information with both clinicians and patients. Kim, et. al., J Bone Min Res, 2016 DOI: /jbmr.2832 To draw an analogy from another field, in 2016 it is virtually inconceivable that a patient discharged from the hospital following a myocardial infarction would not be prescribed a full armamentarium of drugs for secondary cardiovascular prevention (eg, a statin, antihypertensive, and others). Yet what is inconceivable for a patient following a myocardial infarction is the norm in the vast majority of patients discharged from hospital after a hip fracture. Khosla and Shane, J Bone Min Res, 2016 DOI: /jbmr.2888

3 Insanity: doing the same thing over and over again and expecting different results. Albert Einstein When You Have Failed; Try Something Else My Bias is That We Need to Think About Weak Bone and Weak Muscles That Occur in a Given Individual Rather than focusing on a single component, i.e., osteoporosis, sarcopenia, or obesity, an opportunity exists to combine clinical factors thereby allowing improved identification of older adults at risk Such a combination could be termed dysmobility syndrome. Binkley, et. al, Osteoporos Int, 2013: 24: In My Opinion, The Disease is Fracture Osteoporosis, Sarcopenia, Obesity and Other Things Contribute to This I Have NO Evidence To Support a Bone Attack Concept, But it Makes Sense. Consider the Heart Attack Analogy Treatment is Directed at Various Conditions to Reduce Risk For a Potentially Catastrophic Outcome Metabolic Syndrome Advancing age Hyperlipidemia Hypertension Diabetes Obesity Family History Heart Attack Toxins, e.g., tobacco Reduced QOL Healthcare Cost Death The Syndrome Name is Not Important, (Dysmobility, Bone Attack, etc) but The Concept Is Dysmobility Syndrome Advancing age Osteoporosis Sarcopenia Falls, Fractures Diabetes and Disability Obesity Family History Toxins, e.g., tobacco Reduced QOL Healthcare Cost Death Why Do I Believe That Focus Only on Bone, or Only on Muscle, is Missing The Point??

4 Focusing Solely on Bone Identifies Less than Half of Women Who Will Fracture Only 44% of women (and 21% of men) who sustain non-vertebral fractures have osteoporosis by BMD Number of non-vertebral fractures participants in the Rotterdam study; Mean follow-up 6.8 yrs FN BMD at baseline (Female data presented here) 0 Normal BMD Osteopenia Osteoporosis Adapted from Schuit, Bone. 2004;34: Despite the Fact That Approximately 1/6 Fragility Fractures Occur in People With Normal BMD. Our Guidelines are Missing the Point The diagnosis of osteoporosis is established by measurement of BMD or by the occurrence of adulthood hip or vertebral fracture in the absence of major trauma (such as a motor vehicle accident or multiple story fall). NOF Clinician s Guide: 2014 Does This Man Have Osteoporosis? Hx of fall with scalp laceration 2 months prior Severe knee OA, unable to arise from chair without using his arms Slipped in his garage; left hip fracture at age 66; BMI = 34.9 It is Clear That Low Bone Density, i.e., Osteoporosis is Only Part of the Clinical Constellation that Contributes to What is Currently Called Osteoporosis-Related Fracture Think Beyond the Bone L1-L g/cm 2 T-score = +6.4 FN g/cm 2 ; T-score = +0.9 TF g/cm 2 ; T-score = Radius g/cm 2 T-score = +1.9 Fracture Risk Increases Markedly After Age ~70 in Both Men and Women But Bone Mass Does Not Have A Similar Dramatic Decline After Age 70 60% of hip fractures in women occur after the age of 80 Median age for hip fracture in women is ~ 83 years Adapted from Cooper & Melton, Trends Endo Metab, 3:224-, 1992 Rizzoli, et. al, Curr Med Res Opin, 25: , 2009 The Increase in Fracture Risk Includes Something Else in Addition to BMD Kelly, et. al,

5 We Know That Age Powerfully Predicts Fracture Fracture Risk per 1000 person-years Chronologic Age is a Poor Predictor of Functional Status >1.00 BMD (grams/cm 2 ) Age (years) There must be a better way to estimate a patient s fracture risk than simply using age. Adapted from Hui, JCI 1988; 81: Why Do Fractures Increase With Age? Multiple reasons. Falls become common with advancing age ~1/3 rd of adults age 65 and >40% over age 75 fall each year Many osteoporosis-related fractures due to falls Over 90% of hip fractures due to falls An Example of the Importance of Considering Falls in Fracture Risk FRAX does not allow consideration of falls risk or multiple fractures, but the Garvan calculator does 86 yo wf; macular degen, 4 vert fx, 4 falls in last year, 86#, 60 Rizzoli, et. al, Curr Med Res Opin, 25: , 2009 Guideline for falls prevention; AGS/BGS, JAGS 49: , 2001 Falls Risk Factors Predict Hip Fracture Independent of BMD These risk factors include History of falls } Self reported health Surrogates Self reported physical activity Slower walking speed of sarcopenia Is it Sarcopenia/Impaired Function That Actually Predicts Hip Fracture? Masud & Morris. 2001, Age & Ageing 30;Suppl 4:3-7 Geusens et. al., 2010, Therap Advances Musculoskel Dis 2:63-67 Impaired Physical Performance Does Increase Hip Fracture Risk Evaluated the association of physical performance and hip fracture risk in MrOS; 5995 men age 65+ Poor physical function is independently associated with an increased risk of hip fracture in older men. Adapted from Cawthon, et. al., J Bone Miner Res, 2008, 23:

6 To Oversimplify a Complex Process Sarcopenia/Falls Is a Major Part of the Increase in Fracture Risk Currently Ascribed to Age When We Are Thinking About Osteoporosis We Also Need To Consider Sarcopenia and Other Things Sarcopenia: the Age-related Gradual Loss of Muscle mass, Strength and Function Sarc for flesh (muscle), penia for deficiency Term coined in 1989; more recently defined as: The ageassociated loss of skeletal muscle mass and function. a complex syndrome associated with muscle mass loss alone or in conjunction with increased fat mass. Fielding, et. al, J Am Med Dir Assoc 2011; 12: Consequences of Sarcopenia Include: Impaired ability to perform activities of daily living/functional impairment Falls Fractures Reduced quality of life Healthcare costs Death Fielding, et. al, J Am Med Dir Assoc 2011; 12: Impaired muscle strength is highly predictive of incident disability and all-cause mortality in the elderly. Cesari and Pahor, J Nutr Health Aging, 2008; 12: , 2008 Sarcopenia Becomes Common With Advancing Age Prevalence Depends on Definition, Study Population and Method Used Prevalence Summary: It s Common Prevalence depends on the definition, technique(s) used to measure muscle mass/strength and the reference population. Prevalence differs by gender and increases with age: <5% in women age 50-65; increasing to 30% age 80+ Up to 50% in men age 80+ Baumgartner et al. Am J Epidemiol. 1998;147(8): Melton, et. al., J Am Geriatr Soc 2000; 48: Newman, et. al., J Am Geriatr Soc : Delmonico, et. al., J Am Geriatr Soc : Gielen, et. al., Calcif Tissue Int 2012: 91, Rolland et al. J Am Geriatr Soc. 2003; 51: Laurentani, et. al., J Appl Physiol, 2003;95: Janssen, et. al., Am J Epidemiol, 2004;159: Janssen, et. al., J Am Geriatr Soc, 2006;54:56-62 Chien, et. al., J Am Geriatr Soc, 2008;56: Prevalence of Reduced Muscle Strength in Older US Adults Used FNIH definitions to provide national estimates of muscle strength in older adults Looker and Wang, NCHS Data Brief #179, January 2015 Osteoporosis Sarcopenia Pathogenesis is Multifactorial Hormonal declines Are GH/IGF-1, testosterone, estrogen Osteoporosis Increased inflammation IL-6, TNF-alpha, etc, etc. and Sarcopenia Malnutrition the Same Protein, vitamin D Process? Sedentariness/Diseases leading to decreased use Toxin exposure Neuronal loss Reduced muscle bone quality expressed ultimately as reduced function Changes in structure, fat and connective tissue With the Disease Being Fracture? Jensen, J Parenter Enteral Nutr, 32; , 2008

7 Perhaps The Diagnosis Should be Sarco-osteoporosis Women With Hip Fracture Often Have Sarcopenia and Osteoporosis by DXA 313 white women with low-trauma hip fracture Sarcopenia; ALM/Ht 2 < 5.45 kg/m 2 Osteoporosis; Femur T-score -2.5 We show.. A significant association between sarcopenia and osteoporosis in a large sample of hip-fracture women. Data supports preventive strategies and treatment options for sarcopenia and osteoporosis targeting both bone and muscle Binkley and Buehring, J Clin Densitom, 12; , 2009 Adapted from Di Monaco, et. al, Arch Gerontol Geriatr, 52; 71-71, 2011 Interdependency of Bone and Muscle is Not a New Concept The mechanostat model of bone regulation was described in 1960 by Dr. Frost in his Utah Paradigm Holds that bone growth and loss is stimulated by local mechanical elastic deformation of bone due to muscle force. More muscle, more strain, more bone Less muscle, less strain, less bone Frost H.M., The Utah Paradigm of Skeletal Physiology Vols 1 and 2, ISMNI, 1960 Frost, HM. J Bone Miner Metab. 2000; 18: Muscle Talks to Bone Multiple Candidate Myokines Exist Including IGF-1, FGF-2, IL-6, IGFBP-5, Osteonectin, TGF-B1, matrix metalloproteinase, leukemia inhibitory factor, FGF-21, Wnt3a, myostatin, others.. Receptors for IGF-1 and FGF-2 are localized to the periosteum at the muscle-bone interface Molecules should exist that increase muscle mass Some of these myokines likely are bone anabolic AND (by secretion of osteogenic myokines) also Proposed that exercise-induced plasma membrane disruption of improve myofibers releases bone strength FGF-2 Conversely, muscle atrophy may inhibit bone formation via myokines, e.g., myostatin Hamrick, Exerc Sport Sci Rev, 2011; 39:43-47 Bone (Osteocytes) Talks to Muscle Even Bone + Muscle Isn t the Whole Story Obesity Increases Fracture Risk The prime sensors of mechanical strain Strain might also be sensed by osteoblasts, adult muscle cells and even perivascular cells Produce sclerostin, DKK1, frizzled protein, osteocalcin, etc Osteocyte dendrites may directly connect to muscle and the vascular system ASBMR Topical Meeting, July 2012 Global Longitudinal Study 60,393 women age 55 Followed for 2 years Our results demonstrate that obesity is not protective against fracture in postmenopausal women and is associated with increased risk of ankle and upper leg fractures. Compston, et al. Am J Med. 2011, 124:

8 Sarcopenic Obesity Inadequate Muscle Mass/Strength in the Presence of Elevated Body Fat Studenski, ASBMR Annual Meeting, 2011 Baumgartner: ALM/Ht 2 lower than 2 SD below mean young reference and body fat greater than 28% in men and 40% in women FNIH Sarcopenia Project suggests ALM/BMI as a diagnostic criteria for sarcopenia Essentially is muscle mass/weight adjusted for height At a given amount of muscle mass, a higher BMI makes the ALM/BMI ratio look worse Change in ALM/BMI as Fat Mass Increases Assume ALM = 16 kg (~ average for an 80 year old women) Low < per FNIH BMI ALM/BMI Too Little Bone, Too Little Muscle and Too Much Fat is Bad Should the Diagnosis be Osteo-Sarcobesity? Diabetes Almost Certainly Should be Included as a Risk Factor Low Bone Mass Osteoporosis Low Muscle Mass Sarcopenia High Adipose Mass Obesity This Led us to Think About Dysmobility but We Need to Consider Other Things Manitoba, CA clinical data 3518 M/W age 50+ with, and without DM at Time of BMD testing Mean f/u 5.4 years Fx ascertained by ICD code FRAX underestimated observed major osteoporotic and hip fracture risk in diabetics. We conclude that diabetes confers an increased risk of fracture that is independent of FRAX derived with BMD. Giangregorio, et al, J Bone Miner Res, 2012, 27: Osteoarthritis Perhaps Should Also be Included as a Risk Factor Integrating Dsymobility Risk into FRAX is an Ideal Way to Facilitate Clinical Implementation 2412 women and 1452 men; age >45 years Dubbo Osteoporosis Epidemiology Study (DOES) Median follow-up 7.5 years OA by self-report Fx incidence from X-ray reports Women with OA have an increased risk of fragility fracture Fracture risk was significantly higher in women with OA; Mainly observed in osteopenia Falls Sarcopenia Diabetes One year probability of falls (%) Any fall Injurious fall Chan, et al, Osteoarthritis and Cartilage 22; 2014, Symptomatic Osteoarthritis

9 Development of Such a Calculator Will Take Time: Can We Diagnose Dysmobility in Clinic Today? We Could Potentially Diagnose Sarcopenia by Only Measuring The Amount of Muscle Present To define sarcopenia, it is necessary to measure relative muscle mass, since absolute muscle mass is correlated strongly with height. ASM (kg/m 2 ) was calculated as an index of relative skeletal muscle mass, and it is directly analogous to the use of the body mass index for grading relative adiposity. Baumgartner, et. al, Am J Epidemiol, 147; , 1998 Mass-based Diagnostic Approaches Are Not Perfect For Bone (Not Everyone With Osteopenia Has Lost Bone and/or Is At High Fracture Risk) The Same is True for Muscle: Cannot Simply Diagnose Sarcopenia Based on Low Mass (Not Everyone With Low Mass Has Lost Muscle and/or is at High Falls Risk) Example of Why Muscle Mass Should Not Be The Sole Diagnostic Criterion for Sarcopenia Appendicular lean mass/ht 2 cutpoint < 5.45 kg/m 2 ALM/ht kg/m 2 ALM/ht kg/m 2 51 year-old healthy competitive cyclist 86 year-old frail nursing home resident All Current Sarcopenia Consensus Definitions Include Both Muscle Mass and Function Assessment Assessed whether various definitions of sarcopenia predict falls Studied 445 seniors mean age 72 who had detailed falls history over 3 years..our comparative performance exercise of published definitions supports the possibility of a pragmatic approach that may be focused on low appendicular lean mass adjusted for body height alone Bischoff-Ferrari, et. al, Osteoporos Int, DOI /s y, 2015 Cruz-Jentoft, Age Aging, 2010, 39: Fielding, JAMDA, 2011, 12: Studenski, J Gerontol A Biol Sci Med Sci, 2014, 69: I think this is an advantage over osteoporosis; the definition can include BOTH muscle mass and muscle quality

10 Taking Bone Attack to the Clinic. In Addition to Your Usual Osteoporosis Evaluation How many times have you fallen in the past year? Did any of these falls cause injury? Would you please stand up for me? If history of falls, particularly injurious falls and/or cannot arise without use of arms: Likely has sarcopenia or dysmobility and is at increased risk for bone attack So Once We Have Diagnosed Sarcopenia or Dysmobility Syndrome (Or Whatever the Terminology Becomes) What Are We Going to do About it?? Seems Likely That We Will Follow the Current Osteoporosis Paradigm Exercise Potential types of exercises include: Aerobic exercise Progressive resistance training Balance training Flexibility training Physical activity is a modifiable lifestyle behavior, but patients need to be motivated to make changes Evidence supports a beneficial interaction of exercise and protein on muscle There continues to be a lack of good evidence on which exercise regimens improve outcomes of sarcopenia Phu, et. al., 2015, J Clin Densitom, epub Walston, Curr Opin Rheumtol, 2012, 24:623-7; Montero- Fernandez, Eur J Phys Rehab Med, 2013, 49: Exercise per NIA Nutrition Is a Cornerstone of Sarcopenia Treatment Despite the obesity epidemic, remember that Under-nutrition is common ~40% of hip fracture patients have energy/protein malnutrition Inadequate protein intake reduces muscle synthesis ~40% of older adults not meeting current RDA of 0.8 g/kg daily Protein intake of g/kg daily is likely optimal Rizzoli R, J Clin Densitom, 2015, epub

11 Vitamin D The Vitamin D World is in Chaos Anyone That Tells You They Know the Right Answer is Kidding Themselves and You An Example of the Chaos The IOM report makes a positive contribution by grounding its recommendations on the available evidence base.(we are) generally in agreement with these conclusions. Reid IR & Avenell A, JBMR, 26; , 2011 The IOM recommendations for vitamin D fail in a major way on logic, on science and on effective public health guidance.our recommendation to the public is that the IOM report should be taken with a grain of salt Heaney RP & Holick MF, JBMR, 26; , 2011 Where is the Vitamin D Field Today? Experts are passionate and divided 25(OH)D assays remain imperfect and what to measure is not clear The systematic reviews are fatally flawed by assay issues and clinical trial methodology It is not possible to meta-analyze our way out of this mess Guidelines are not concordant Physicians and patients hear differing opinions We are providing patient care; Do No Harm Goldilocks principle; not too hot or too cold, just right Our Ancestors Were Highly Sun-exposed Due to Minimal Oral Intake Plus Low Sun Exposure/Sun Avoidance, Low Vitamin D Status is Common Worldwide Eaton S, Osteoporos Int, 17(suppl 2): S2-3, 2006

12 The Question is How to Define Low What is Vitamin D Deficiency or Insufficiency? A Fundamental Challenge to Defining Vitamin D Inadequacy is That There is No Direct Way to Determine if the Vitamin D Status of an Individual is Optimal i.e., there is no TSH equivalent to define a person s vitamin D status It is Widely Accepted that 25(OH)D is the Measurement to Define Vitamin D Status Current Dogma Holds That to Assess Vitamin D Status: Measure 25(OH)D After careful consideration of the evidence, the Committee concluded that.. serum 25(OH)D levels were the most useful marker of vitamin D exposure. Ross AC, et. al, J Clin Endocrinol Metab, 2011, 96:53 58 Insufficiency ~ below 12 ng/ml ~ ng/ml?? ~ below 30 nmol/l ~ nmol/l?? The cutpoints are very controversial IOM 2010 guidelines endorsed 20 ng/ml (50 nmol/l) but the Endocrine Society endorsed 30 ng/ml (75 nmol/l) These Cutpoints are Driven by Lab Tests No Assay is Perfect; 25(OH)D is Not Different Be Aware That 30 ng/ml is NOT 30 ng/ml +2SD VDSP recommends that 25(OH)D assays perform with a CV <10% 30.6 CV 10% 9% 8% 7% 6% 5% 4% 3% 2% 1% SD Acceptable 30 Serum aliquots sent to 8 clinical labs for 25(OH)D measurement Data from Binkley, et al., Clin Chim Acta, 411: , 2010 If your lab is meeting this target, an individual patient 25(OH)D result of 30 ng/ml is actually ng/ml Lappe & Binkley, J Clin Densitom, 2015 epub; doi: /j.jocd

13 A more fundamental question is WHY are we using 25(OH)D to define vitamin D status Why was 25(OH)D selected as the test to define an individual s vitamin D status? There are several reasons why measurement of 25(OH)D 3 was embraced as an indicator of vitamin D status. First, it is the most abundant of the vitamin D family in the blood. D 3 is usually 1-5 ng/ml, while 25(OH)D 3 is ~30 ng/ml. Because of the amount and its affinity for DBP, the first easy assay was 25(OH)D 3 by protein binding, now by antibody and MS/MS. 1,25(OH) 2 D would certainly be the functional form to measure, but it is in vanishingly small amounts and it varies according to more than 1 factor, i.e., calcium intake, PTH, etc. More important is that the assays are (not good). Personal communication, Prof. Hector DeLuca, 2015 Why was 25(OH)D selected as the test to define an individual s vitamin D status? Adequate assessment of vitamin D status, it seems to me, requires a combination of D 3 itself, together with 25(OH)D 3 [or total 25D]. The importance of measuring D 3 relates to the fact that D 3 itself enters many cells, and its serum concentration may limit what the tissues concerned can do with it. To me 1,25(OH) 2 D is a measure of calcium status, not vitamin D status. Personal communication, Prof. Robert Heaney, 2015 There is a Vast Array of Vitamin D Metabolites Some of these other metabolites possess vitamin D physiologic effects Examples may include 3-epi 25(OH)D, cholecalciferol and 24, 25(OH) 2 D Could Failure to Use Standardized Assays Alter The Target 25(OH)D? What if an individual study s 25(OH)D results were biased 12% low or 12% high? Note: Not unreasonable possibilities based on comparison with DEQAS in the past What About Free or Bioavailable Vitamin D Metabolites? It is often assumed (perhaps correctly) that only the free fraction of hormones can enter cells and thereby cause effects Using the same dataset, it could be concluded that PTH plateaus at ~20 ng/ml or ~35 ng/ml Binkley, et. al, presented at IOF Malaga, 2016 & submitted for publication

14 Calculated Free 25(OH)D Does Not Agree with a Direct Immunoassay Measurement Compared calculated free 25(OH)D determined using method reported by Bikle (JCEM 1986) with free measured by immunoassay Calculated free 25(OH)D levels varied considerably from direct measurements of free Directly measured free 25(OH)D concentrations were related to ipth, but calculated estimates were not Current algorithms to calculate free 25(OH)D may not be accurate The 25(OH)D assays are imperfect, further standardization is needed, and it is not entirely clear that sole measurement of 25(OH)D is the right analyte AND Current Vitamin D Systematic Reviews/Meta-Analyses are Flawed Schwartz, et al. J Clin Endocrinol Metab, 2014; 99: Nutrients Are Not the Same as Drugs However, most RCTs of D supplementation have NOT required low vitamin D status for study inclusion There is Between Individual Variation in 25(OH)D Response to a Given Oral Dose No RCTs have used a treat to target strategy Of these 20 women receiving 2500 vitamin D3 daily, 8 had NO chance of a positive response, 4 remained low and 4 went too high. Thus 4/20 were ideally supplemented Clinical Trials and Subsequent Meta- Analyses Need to Focus on Biology Not Just Trial Methodology What Do I Do Clinically?? The question of how much vitamin D is enough is likely to remain muddled as long as meta-analyses focus on trial methodology rather than on biology Heaney, RP, NEJM, 2012, 367, Finally, the examples reported here highlight the importance of suspending publication of metaanalyses based on unstandardized 25(OH)D results. Binkley, et. al, presented at IOF Malaga, 2016 & submitted for publication

15 Vitamin D Important for Bone & Muscle Nobody knows the right answer re: vitamin D USPSTF and AGS recommend vitamin D to reduce falls risk Daily intake = enough The RDA ( IU) is Not Enough Does Not Assure 20 or 30 ng/ml in a Given Individual Mean 25(OH)D 46 ng/ml Luxwolda, et. al., B J Nutr, V 108 / Issue 09 / November 2012, pp Ross, et. al., J Clin Endocrinol Metab, 96; 53-58, 2011 Postmenopausal women with 25(OH)D < 30 ng/ml received 2500 IU D 3 /d for 4-6 mo ~40% remained <35 ng/ml Binkley, et. al., Data currently unpublished Whether You Wish to Aim for 20 ng/ml or 30 ng/ml, Use Moderation and Consider Assay Variability What s a Clinician to Do? Aim High! To Maintain Serum 25(OH)D of 20 ng/ml or 30 ng/ml Measured True Value Maintain Maximum 25(OH)D 20 ng/ml ~10 to ~ 35 ng/ml ~35 ng/ml 50 ng/ml 25(OH)D 30 ng/ml ~15 to ~45 ng/ml 45 ng/ml 60 ng/ml Recognize that the reported value may be low: with this approach, the maximum is likely to be ~50 to ~60 ng/ml, below that attainable by UV exposure Rarely Use 50,000 IU Doses of Vitamin D Human Physiology Expects Daily D 3 Input, Not Bolus Doses We don t really know what we are doing to vitamin D metabolism by providing huge, non-physiologic doses Heaney, et. al., Nutr Rev; 73(1):51 67, community dwelling women Age ,000 IU D 3 orally or placebo in fall or winter Falls and fractures 137 had 25(OH)D measured serially Median 25(OH)D ~50 ng/ml A temporal pattern of falls was observed with an increase only in the first 3 months annual oral administration of high-dose cholecalciferol results in an increased risk of falls and fractures. Sanders, et. al., JAMA, 303; , 2010

16 Vitamin D Summary: September 2016 The field is in chaos.. Vitamin D inadequacy (however defined) is common Vitamin D is cheap and virtually side effect free Can t pick a single dose to assure whatever you believe to be vitamin D adequacy Daily dosing makes physiologic sense Ancestral human 25(OH)D mean is ~ 40 ng/ml Our current 25(OH)D measurements are imperfect Assay improvements are needed; progress being made RCTs with better study designs need to be conducted; This is not happening yet; expect chaos to continue In Summary: Treat the Person, Not Just Their Bones The good physician treats the disease; the great physician treats the patient who has the disease. Sir William Osler Sarcopenia/Dysmobility/Bone Attack What Can We Do Today? Recognize the problem; Convey the message that bone attacks are NOT OK Reduce falls Ask How many times have you fallen in the past year? Ask to stand up without use of arms The usual falls risk reduction strategies including a PT consult Recognize that obesity increase risk Food is a good thing; but excess is not Nutritional supplements improve outcomes after hip fracture Optimize vitamin D status 2,000 IU daily is a reasonable place to start Need to measure 25(OH)D in those with falls/fractures Sarcopenia/Dysmobility/Bone Attack What Can We Do Today? Use osteoporosis medications to treat the bones Consider the Garvan calculator to advise re: fracture risk in patients with sarcopenia/falls Many patients know that osteoporosis drugs are bad 68 yo White woman, wt 200#, ht 64, T-score -2.0, wrist Fx, 3 falls last year A 45%/21% risk sounds different than 17%/3% Treatment After Bone Attack Reduces Mortality and NH Readmission 124 patients with hip fracture 12 mo of high-intensity weight lifting exercise and targeted treatment of balance, osteoporosis, nutrition, vitamin D/calcium, depression, cognition, vision, home safety, polypharmacy and social support vs. usual care Note: Usual care included inpatient orthogeriatric and allied health consultation followed by 6-12 weeks of standard inpatient/outpatient physical therapy. Mortality NH Re-admit ADL decline was less and fewer use of assistive devices The intervention reduced mortality, nursing home admissions and ADL dependency compared with usual care. Adapted from Singh, et. al, JAMDA, 13: 24-30, 2012 Summary Bone and muscle are interconnected in the pathophysiology leading to what are currently called osteoporosis-related fractures We should be thinking not just about osteoporosis and not just about sarcopenia, but rather about dysmobility syndrome which has adverse outcomes of falls & fractures The vitamin D world is in chaos Vitamin D DEFICIENCY leads to weak bone and muscle, but it is unknown what role(s), if any, vitamin D INADEQUACY plays in bone health and muscle function

17 Thank You