SERUM 25HYDROXYVITAMIN D CONCENTRATIONS AND RISK FOR HIP FRACTURES

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SERUM 25-HYDROXYVITAMIN D CONCENTRATIONS AND RISK
FOR HIP FRACTURES

• Jane A. Cauley, DrPH Andrea Z. LaCroix, PhD
  LieLing Wu, MS Mara Horwitz, MD Michelle E.
  Danielson, PhD Doug C. Bauer, MD Jennifer S.
  Lee, MD Rebecca D. Jackson, MD John A. Robbins,
  MD Chunyuan Wu, MS Frank Z. Stanczyk, PhD
  Meryl S. LeBoff, MD Jean Wactawski-Wende, PhD
  Gloria Sarto, MD Judith Ockene, PhD and Steven
  R. Cummings, MD
• ANNALS OF INTERNAL MEDICINE
• 19 August 2008 Volume 149 Issue 4 Pages
  242-250
• Usman J. Rahmat
• Georgetown University Hospital
• September 23, 2008

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BACKGROUND

• Cholecalciferol D3
• Calcidiol 25(OH)D or 25D
• Calcitriol 1,25(OH)2D3 or 1,25D3

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HIP FRACTURES

• An estimated 340,000 hip fractures occur each
  year..
• Nine of 10 hip fractures occur in patients aged
  65 years and older, and 3 of 4 occur in women.
• White females have been reported to be twice as
  likely to fracture their hips than black and
  Hispanic females.
• The rate of fractures is low in adolescent and
  young athletic populations, estimated to be less
  than 2 of all hip fractures (one hundredth of
  adult hip fractures).

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MORBIDITY/MORTALITY

• Reported overall mortality rate of hip fractures
  is 15-20, yet in older persons this can increase
  to 36 over the year following hip fracture.
• Morbidity associated with hip fracture is
  staggering, especially in older persons.
• development of deep vein thrombosis
• pulmonary embolism
• Pneumonia
• muscular deconditioning
• Morbidity from surgical procedures -
  complications of anesthesia, postoperative
  infection, loss of fixation

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BACKGROUND

• Vitamin D deficiency is common in older adults
• In Homebound population
• General medicine inpatients
• Community Dwelling women admitted to hospital
  with acute hip fracture

One Prospective study reported no relationship
between serum vitamin D concentration and
fractures WHI Calcium-Vitamin D trial A second
Prospective Study reported a significant lower
risk for hip fractures with 25(OH) vitamin D
concentrations greater than 60 mmol (NHANES III )
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DESIGN

• Nested Case Control Study
• 400 case-patients with adjudicated incident hip
  fractures
• 400 control participants

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OBJECTIVE

• Whether low serum 25 (OH) vitamin D
  concentrations are associated with a higher risk
  for hip fractures in community-dwelling women and
  whether this relationship may be mediated by poor
  physical functioning, frailty, falls, sex-steroid
  hormones, renal function, or bone turnover

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STUDY DESIGN

• Nested Case-Control Study design
• Multicenter
• All regions of the United States 40 clinical
  centers
• All types of institutions community hospitals to
  large tertiary medical centers
• Enrollment Criteria
• Postmenopausal
• Unlikely to move or die within 3 yrs
• Were not enrolled in WHI clinical trials
• Were not currently participating in any other
  clinical trial

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STUDY POPULATION

• Study population came from the Womens Health
  Initiative-Observational Study (WHI-OS) a
  prospective cohort study that enrolled 93,676
  women between 1994-1998 at 40 US clinical centers
• Age ranging from 50 yo to 79 yo

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EXCLUSION CRITERIA

• Women with history of hip fracture
• Women receiving hormone therapy up to 1 yr before
  enrollment
• Women currently receiving
• Androgens
• Selective estrogen receptor modulators
• Antiestrogens
• Bisphosphonates
• Calcitonin
• PTH

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FOLLOW UP/OUTCOME ASCERTAINMENT

• Women sent questionnaires annually to report any
  hospitalizations and other outcomes (including
  fractures)
• As of August 2004 median follow up was 7.1
  years (range .7-9.3 years)
• 3.7 pts withheld or lost to F/U
• 5.3 pts Had Died
• Medical records reviewed to verify cases of hip
  fractures
• Pathologic Hip Fracture Patients were excluded

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STUDY DESIGN

• 39,793 eligible participants
• 404 women had a hip fracture - CASE
• 400 women randomly selected - CONTROL
• For each case pt selected 1 control pt
• Within 1 yr of age
• With matching race or Ethnicity
• Blood drawn within 120 days of Case Pt

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STUDY DESIGN

• Divided Clinical Centers into 3 geographic region
• Northern (gt 40 degrees N)
• Middle (35-40 degrees N)
• Southern (lt 35 degrees N)
• Clinical interviewers recorded current use of
  prescription medication by direct inspection of
  all medical containers
• Assessed Total Vitamin D and Calcium
• Elemental preparations
• Dietary intake

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STUDY DESIGN

• QUESTIONAIRRE
• Ascertain Date of Birth
• Hx of any fracture after age 55 yo
• Smoking
• Parental Hx of hip fracture
• Self-rated Health status
• Alcohol consumption
• Physical activity
• Physical function (RAND Short Form-36 physical
  function scale)

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FRAILTY SCORE

• Woman were considered frail if she reported 3 or
  more indicators
• Self reported muscle weakness/impaired walking
  speed (RAND lt 75)
• Exhaustion (RAND lt 50)
• Low physical activity (lowest quartile)
• Unintended weight loss between baseline and 3 yrs
  follow up (22 lbs)

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LABORATORY PROCEDURES

• 12 hr fasting blood sample at baseline visit
• Samples all held at -80 degree C
• Measured Serum 25(OH) vitamin D and sex steroid
  hormone levels
• Estradiol
• Testosterone
• Sex Hormone Binding Globulin
• Serum Cystatin C
• C terminal telopeptide of type 1 collagen

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STATISTICAL ANALYSIS

• Chi square T tests to compare baseline
  characteristics between case-patients with hip
  fractures and matched controls
• Assigned 25(OH) vitamin D concentrations to
  quartile categories defined on the basis of the
  distribution of the control participants
• Calculated Odds Ratios and 95 CIs from
  conditional regression models across quartiles

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RESULTS

• Average age 71 yrs old
• 95 Caucasian
• CASE Patients
• Lower BMI
• Performed less physical activity
• Fair or poor health status
• More likely to report oral corticosteroid use
• Poor physical function
• Increased smoking
• More likely to be considered Frail

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RESULTS

• CASE PATIENTS
• LOWER CALCIUM INTAKE
• LOWER SEX-STEROID HORMONE LEVELS
• HIGHER CYSTATIN C
• HIGHER BONE RESORPTION MARKER LEVELS

- Hormone therapy use, Alcohol intake, Use of
Vitamin D supplements or Dietary Vitamin D,
personal or family history of fracture,
geographic location, and bone formation DID NOT
differ between Case-patients and control
participants
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RESULTS

• Mean 25(OH) vitamin D levels were lower in case
  patients than control patients
• CASE 55.95 (SD 20.28)
• Control 59.60 (SD 18.05)

- P Value 0.007
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COMPARISONS ACROSS QUARTILES

• Increasing 25 (OH) vitamin D quartiles
• Decreased nonwhite, obese, and frail women
• Decreased fair or poor health status
• Physical function and physical activity increased
• Increased Vitamin D supplements, vitamin D
  intake, calcium intake
• Decreased sex-steroid, Cystatin C, and bone
  resorption

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Serum 25(OH) Vitamin D and Hip fracture

• UNADJUSTED ODDS RATIO FOR INCIDENT HIP FRACTURES
  PER 25 NMOL DECREASE IN CONC 1.30
• 95 CI 1.07 TO 1.58
• QUARTILE 1 VS QUARTILE 4 1.70 (CI, 1.05 TO 2.79
• THRESHOLD OF LESS THAN 50 NMOL - NOT
  STATISTICALLY SIGNIFICANT (P.78)

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POTENTIAL MEDIATORS

• FALLS
• PHYSICAL FUNCTIONING
• FRAILTY
• SEX STEROID HORMONES
• Serum C-terminal telopeptide of type 1 collagen

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RESULTS

• FULLY ADJUSTED ODDS OF FRACTURE FOR WOMEN WITH
  THE LOWEST CONCENTRATIONS (QUARTILE 1) 1.72 (
  CI, .98 TO 3.02)
• P 0.060
• P FOR TREND 0.029

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FINDINGS

• Women at lowest 25(OH) vitamin D concentrations
  (lt 47.6 nmol/l) had significantly greater
  increased risk for subsequent hip fracture during
  the next 7 yrs than women with the highest
  concentrations (gt 70.7 nmol/L)
• P FOR TREND 0.029

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DISCUSSION

• Results consistent with NHANES III (Third
  National Health and Nutritional Examination
  Survey)
• Results consistent with cohort study of Swedish
  women

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DISCUSSION

• Increased C Terminal telopeptide of type 1
  collagen in those with lower Calcidiol levels
• Case patients with hip fracture had lower
  physical function scores
• Higher Calcidiol concentrations associated with
  higher physical function scores

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DISCUSSION

• The relationship between 25(OH) vitamin D
  concentrations and hip fracture was independent
  of
• Geographic Location
• Obesity

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WHAT IS THE OPTIMAL CALCIDIOL CONCENTRATION?

• OPTIMAL CALCIDIOL CONCENTRATION HAS BEEN DEFINED
  AS THAT AT WHICH SERUM PARATHYROID HORMONE LEVELS
  PLATEAU IN THE NORMAL RANGE
• THE OPTIMUM SERUM 25(OF) VITAMIN D CONCENTRATION
  NEEDED TO MAINTAIN BONE HEALTH HAS NOT BEEN
  ESTABLISHED

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DISCUSSION

• NHANES - Studies show that optimal calcidiol
  threshold based on bone mineral density levels
  found to be at least 78 nmol/L
• Randomized trials of vitamin D supplementation
  that brought concentration up to 75 to 102.5 nmol
  significantly lower fracture rates

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DISCUSSION

• WHI calcium-vitamin D trial mean serum 25(OH)
  vitamin D concentrations that did not reach
  threshold showed no overall effect of fractures
• Determined no significant relationship between
  25(OH) vitamin D concentration and fracture

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STUDY LIMITATIONS

• BLOOD DRAW SCHEDULE
• RACE
• BONE MINERAL DENSITY
• PARATHYROID HORMONE
• FEW WOMEN WITH SERUM 25(OH) VITAMIN D
  CONCENTRATION GREATER THAN 75 NMOL/L
• OVER-READING

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CONCLUSION

• RELATIONSHIP BETWEEN LOW 25(OH) VITAMIN D
  CONCENTRATION ARE ASSOCIATED WITH AN INCREASED
  RISK FOR HIP FRACTURE IN COMMUNITY-DWELLING WOMEN

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CLINICAL PRACTICE

• SERUM 25(OH) VITAMIN D CONCENTRATION
• VITAMIN D SUPPLEMENTATION -
• http//www.mayoclinic.com/health/vitamin-d/NS_pati
  ent-vitamind
• VITAMIN D TOXICITY
• BENEFITS OF VITAMIN D

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