Treatment To Prevent Fractures in Men and Women With Low Bone Density or Osteoporosis: An Update

1
Treatment To Prevent Fractures in Men and Women
With Low Bone Density or Osteoporosis An Update

• Prepared for
• Agency for Healthcare Research and Quality (AHRQ)
• www.ahrq.gov

2
Outline of Material

• Introduction to low bone density (LBD)
• Systematic review methods
• The clinical questions addressed by the CER
• Results of studies and evidence-based conclusions
  on the comparative effectiveness and safety of
  treatments to prevent fractures in postmenopausal
  women with osteoporosis
• Gaps in knowledge and future research needs
• What to discuss with patients

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
3
Introduction to Osteoporosis

• Approximately 52 million people in the United
  States are affected by osteoporosis or LBD.
• Osteoporosis is a severe form of LBD especially
  common in postmenopausal women.
• It is a systemic skeletal disease characterized
  by decreasing bone mass and deterioration of the
  microarchitecture of bone tissue.
• It leads to increases in susceptibility to
  fracture.
• Clinical diagnosis of osteoporosis may be based
  on the results of bone mineral density (BMD)
  measurement with dual energy x-ray absorptiometry
  (DXA).

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm. NIH Consensus Development Panel on
Osteoporosis Prevention, Diagnosis, and Therapy.
JAMA 2001285(6)785-95. PMID 11176917. Sasser
AC, Rousculp MD, Birnbaum HG, et al. Womens
Health Issues 200515(3)97-108. PMID 15894195.
4
Classifications of Osteoporosis andLow Bone
Density

• BMD is classified according to the T-score, which
  is the number of standard deviations above or
  below the mean BMD for healthy adults, as
  determined by DXA.
• A T-score of -2.5 or less is classified as
  osteoporosis.
• A T-score between -2.5 and -1.0 is considered LBD
  (also known as osteopenia).
• A T-score of -1 or greater is considered normal.

Kanis JA, Melton LJ 3rd, Christiansen C, et al. J
Bone Miner Res 19949(8)1137-41. PMID
7976495. National Osteoporosis Foundation.
Clinicians Guide To Prevention and Treatment of
Osteoporosis. Available at www.nof.org/sites/defau
lt/files/pdfs/NOF_ClinicianGuide2009_v7.pdf. Nelso
n HD, Haney EM, Dana T, et al. Ann Intern Med
2010153(2)1-11. PMID 20621892. Newberry SJ,
Crandall CC, Gellad WG, et al. Comparative
Effectiveness Review No. 53. Available at
ww.effectivehealthcare.ahrq.gov/lbd.cfm.
5
Risk Factors for Osteoporosis (1 of 2)

• Risk factors include (but are not limited to)

• Increasing age
• Female sex
• Postmenopause for women
• Hypogonadism or premature ovarian failure
• Ethnic background (risk is greater for whites)
• Low body weight
• Previous fracture due to minimal trauma
• Parental history of hip fracture

• Rheumatoid arthritis
• Low BMD
• Current smoking
• Alcohol intake (3 or more drinks per day)
• Vitamin D deficiency
• Low calcium intake
• Hyperkyphosis
• Falling
• Immobilization

National Osteoporosis Foundation. Clinicians
Guide To Prevention and Treatment of
Osteoporosis. Available at www.nof.org/sites/defau
lt/files/pdfs/NOF_ClinicianGuide2009_v7.pdf. Newbe
rry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
6
Risk Factors for Osteoporosis (2 of 2)

• Risk is also increased with the chronic use of
  some medications, including, but not limited to
• Glucocorticoids
• Anticoagulants
• Anticonvulsants
• Aromatase inhibitors
• Cancer chemotherapeutic drugs
• Gonadotropin-releasing hormone agonists

National Osteoporosis Foundation. Clinicians
Guide To Prevention and Treatment of
Osteoporosis. Available at www.nof.org/sites/defau
lt/files/pdfs/NOF_ClinicianGuide2009_v7.pdf. Newb
erry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
7
Predicting Fracture Risk

• Risk scoring methods combine clinical risk
  factors with BMD testing results.
• One such tool is the Fracture Risk Assessment
  Tool (FRAX).
• FRAX was developed by the World Health
  Organization.
• It uses race- and nation-specific risk factors,
  combined with patient-specific BMD data (at the
  femoral neck), to estimate the absolute 10-year
  risk of major osteoporotic fractures.

Kanis JA, Johansson H, Oden A, et al. Eur J
Radiol 200971(3)392-7. PMID 19716672. Kanis
JA, Johnell O, Oden A, et al. Osteoporos Int
200819(4)385-97. PMID 18292978. Kanis JA, Oden
A, Johnell O, et al. Osteoporos Int
200718(8)1033-46. PMID 17323110. Lewiecki EM,
Binkley N. Endocr Pract 200915(6)573-9. PMID
19491062. Newberry SJ, Crandall CC, Gellad WG, et
al. Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm. World Health Organization Collaborating
Centre for Metabolic Bone Diseases. WHO Fracture
Risk Assessment Tool. Available at
www.shef.ac.uk/FRAX.
8
Interventions To Prevent Osteoporotic Fracture

• Interventions to prevent osteoporotic fracture
  include
• Pharmacologic agents
• Dietary and supplemental vitamin D and calcium
• Weight-bearing exercise
• These interventions have also been studied and
  used (with less frequency) in patients with
  osteopenia (T-score between -2.5 and -1.0).

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
9
Pharmacologic Agents To PreventOsteoporotic
Fracture

• Pharmacologic agents investigated in this
  systematic review include
• Antiresorptive Agents
• Bisphosphonates alendronate, risedronate,
  zoledronic acid, and ibandronate
• Estrogen in the form of menopausal hormone
  therapy (MHT)
• Selective estrogen receptor modulators
  raloxifene
• Biologic agents denosumab
• Anabolic Agents
• Peptide hormones teriparatide
• Not all drugs currently approved by the U.S. Food
  and Drug Administration (FDA) for treating
  patients with LBD were required to demonstrate
  reduction in fracture risk (e.g., the peptide
  hormone calcitonin).
• Furthermore, approval of a different dose,
  frequency, or route of administration does not
  require demonstration of reduced fracture risk.
• There are no new findings about calcitonin in the
  report described here.

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
10
Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness Review (CER) Development

• Topics are nominated through a public process,
  which includes submissions from health care
  professionals, professional organizations, the
  private sector, policymakers, members of the
  public, and others.
• A systematic review of all relevant clinical
  studies is conducted by independent researchers,
  funded by AHRQ, to synthesize the evidence in a
  report summarizing what is known and not known
  about the select clinical issue. The research
  questions and the results of the report are
  subject to expert input, peer review, and public
  comment.
• The results of these reviews are summarized into
  Clinician Research Summaries and Consumer
  Research Summaries for use in decisionmaking and
  in discussions with patients. The Summaries and
  the full report, with references for included and
  excluded studies, are available at
  www.effectivehealthcare.ahrq.gov/lbd.cfm.

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
11
Clinical Questions Addressed by the CER (1 of 5)

• Key Question (KQ) 1 What are the comparative
  benefits in fracture reduction among the
  following therapeutic modalities for LBD
• Bisphosphonate medications, specifically
• Alendronate (Fosamax, oral)
• Risedronate (Actonel oral once-a-week)
• Ibandronate (Boniva)
• Zoledronic acid (Reclast, Zometa, oral and
  intravenous)
• Denosumab (Prolia)
• Menopausal estrogen therapy for women (numerous
  brands and routes of administration)
• Parathyroid hormone (PTH)
• 1-34 (teriparatide Forteo)
• Selective estrogen receptor modulators (SERMs),
  specifically
• Raloxifene (Evista)
• Calcium
• Vitamin D
• Combinations or sequential use of above
• Exercise in comparison to the agents above

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
12
Clinical Questions Addressed by the CER (2 of 5)

• KQ 2 How does fracture reduction resulting from
  treatments vary between individuals with
  different risks for fracture as determined by the
  following factors
• BMD
• FRAX or other risk-assessment score
• Prior fractures (prevention vs. treatment)
• Age
• Sex
• Race/ethnicity
• Glucocorticoid use
• Other factors (e.g., community dwelling vs.
  institutionalized, vitamin D deficient vs. not)

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
13
Clinical Questions Addressed by the CER (3 of 5)

• KQ 3 Regarding treatment adherence and
  persistence
• What are the adherence and persistence to
  medications for the treatment and prevention of
  osteoporosis?
• What factors affect adherence and persistence?
• What are the effects of adherence and persistence
  on the risk of fractures?
• ?Adherence Compliance, which is the extent to
  which a patient acts in accordance with the
  prescribed interval and dose of a dosing regimen
  (Cramer et al., 2008).
• Persistence The duration of time from
  initiation to discontinuation of therapy (Cramer
  et al., 2008).

Cramer JA, Roy A, Burrell A. Value Health
200811(1)44-7. PMID 18237359. Newberry SJ,
Crandall CC, Gellad WG, et al. Comparative
Effectiveness Review No. 53. Available at
www.effectivehealthcare.ahrq.gov/lbd.cfm.
14
Clinical Questions Addressed by the CER (4 of 5)

• KQ 4 What are the short- and long-term harms
  (adverse effects) of the above therapies (when
  used specifically to treat or prevent
  LBD/osteoporotic fracture), and do these vary by
  any specific subpopulations (e.g., the
  subpopulations identified in KQ 2)?

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
15
Clinical Questions Addressed by the CER (5 of 5)

• KQ 5 With regard to treatment for preventing
  osteoporotic fracture
• How often should patients be monitored (via
  measurement of BMD during therapy, how does bone
  density monitoring predict antifracture benefits
  during pharmacotherapy, and does the ability of
  monitoring to predict antifracture effects of a
  particular pharmacologic agent vary among the
  pharmacotherapies?
• How does the antifracture benefit vary with
  long-term continued use of pharmacotherapy, and
  what are the comparative antifracture effects of
  continued long-term therapy with the various
  pharmacotherapies?

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
16
Summary of Study Characteristics Evaluated in the
Effectiveness Review PICOTS Framework

• Population Adults over 18, including healthy
  adults, those with LBD, those with osteoporosis,
  and adults at risk of LBD and osteoporosis due to
  chronic use of glucocorticoids or as a result of
  a condition associated with LBD (e.g., rheumatoid
  arthritis, cystic fibrosis, Parkinsons disease)
• Interventions Pharmacological interventions for
  prevention or treatment of osteoporosis approved
  or soon to be approved by the (FDA), calcium,
  vitamin D, or physical activity
• Comparators Placebo, other doses, other agents
  in the same or another class
• Outcomes Vertebral, hip, and total fractures
• Fractures reported as outcomes, not as adverse
  events
• Timing Minimum of 6 months
• Setting All settings

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
17
Modes of Results Reporting and Statistical
Analysis in the CER (1 of 2)

• 95 Confidence Interval (95 CI) The range of
  statistically valid results that will include the
  true population mean in 95 of 100 repeated
  experiments.
• Mean difference (MD) The difference between
  treatment and comparison group means.
• Standardized mean difference (SMD) is the mean
  difference expressed in units of standard
  deviations. It is a method for normalizing
  results to a uniform scale for pooled analysis,
  when different scales are used in trials.
• For MD and SMD, the result is statistically
  significant (p lt 0.05) when the 95 CI does not
  include 0.0, which is the point of no difference
  between groups.
• Odds Ratio (OR) The ratio of the odds of an
  event in the treatment group to the odds of the
  event in the comparison group.
• Odds are the number of individuals in the group
  having an event divided by the number of
  individuals not having the event (Odds with/
  without with without total in the group).
• For OR, the result is statistically significant
  at p lt 0.05 when the 95 CI does not include 1.0,
  which is the point of equal odds for both groups.

Higgins JPT, Green S, eds. Cochrane handbook for
systematic reviews of interventions. Version
5.1.0. Available at www.cochrane-handbook.org. New
berry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
18
Modes of Results Reporting and Statistical
Analysis in the CER (2 of 2)

• Absolute Risk Difference The absolute value of
  the mathematical difference between the rates
  (risk) of an event in the treatment and
  comparison groups.
• ARD ARCART
• Number Needed To Treat or Harm (NNT, NNH) The
  number of patients to be treated to observe
  benefit or harm in one patient more than seen in
  the comparison group. The number of patients to
  be treated in order to find a benefit or harm
  attributable to the intervention.
• NNT or NNH ARCART-1 for a benefit or adverse
  event, respectively
• Number of attributable events per 1,000 1,000 x
  ARCART

Higgins JPT, Green S, eds. Cochrane handbook for
systematic reviews of interventions. Version
5.1.0. Available at www.cochrane-handbook.org. New
berry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
19
Rating the Strength of Evidence From the CER

• The strength of evidence was classified into four
  broad categories

High Further research is very unlikely to change the confidence in the estimate of effect.
Moderate Further research may change the confidence in the estimate of effect and may change the estimate.
Low Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.
Insufficient Evidence either is unavailable or does not permit estimation of an effect.
Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
20
Benefits of Medications (1 of 2 )

• The table below indicates whether the medications
  specified reduce fracture risk for postmenopausal
  women with osteoporosis and the strength of
  evidence (high, moderate, or low) in support of
  each conclusion.

Medication Medication Vertebral Nonvertebral Hip Wrist
Bisphosphonates Alendronate ? High High ? High ? Low
Bisphosphonates Risedronate ? High ? High ? High ? Low
Bisphosphonates Zoledronic acid ? High ? High ? High Not specified
Bisphosphonates Ibandronate ? High Not specified Not specified Not specified
Denosumab Denosumab ? High ? High ? High Not specified
Teriparatide Teriparatide ? High ? Moderate Not specified Not specified
Raloxifene Raloxifene ? High ?High ? High ? High
?Risedronate-mediated wrist fracture risk did not reach the conventional level of statistical significance. ? reduced fracture risk ? did not reduce fracture risk NSD no statistically significant difference ?Risedronate-mediated wrist fracture risk did not reach the conventional level of statistical significance. ? reduced fracture risk ? did not reduce fracture risk NSD no statistically significant difference ?Risedronate-mediated wrist fracture risk did not reach the conventional level of statistical significance. ? reduced fracture risk ? did not reduce fracture risk NSD no statistically significant difference ?Risedronate-mediated wrist fracture risk did not reach the conventional level of statistical significance. ? reduced fracture risk ? did not reduce fracture risk NSD no statistically significant difference ?Risedronate-mediated wrist fracture risk did not reach the conventional level of statistical significance. ? reduced fracture risk ? did not reduce fracture risk NSD no statistically significant difference ?Risedronate-mediated wrist fracture risk did not reach the conventional level of statistical significance. ? reduced fracture risk ? did not reduce fracture risk NSD no statistically significant difference
Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
21
Benefits of Medications (2 of 2)

• Regarding the use of calcium in combination with
  the bisphosphonates, one head-to-head trial found
  that adding calcium to alendronate treatment
  reduced the risk of any type of clinical fracture
  when compared with alendronate alone.
• Strength of Evidence Low

22
Benefits of Medications in Subpopulations
Patient Population Pharmacotherapies Pharmacotherapies Pharmacotherapies Strength of Evidence
Medications that reduce overall fracture risk in the given patient populations Medications that reduce overall fracture risk in the given patient populations Medications that reduce overall fracture risk in the given patient populations Medications that reduce overall fracture risk in the given patient populations Medications that reduce overall fracture risk in the given patient populations
Patients with high risk for fracture (including postmenopausal women with osteoporosis) Alendronate Ibandronate Risedronate Zoledronic acid Denosumab Teriparatide Raloxifene High
Patients treated with glucocorticoids Patients treated with glucocorticoids Alendronate Teriparatide Risedronate Alendronate Teriparatide Risedronate Moderate to High
Patients with a higher risk of falling (e.g., patients with hemiplegia, Alzheimers disease, or Parkinsons disease) Patients with a higher risk of falling (e.g., patients with hemiplegia, Alzheimers disease, or Parkinsons disease) Alendronate Vitamin D Risedronate Alendronate Vitamin D Risedronate Moderate
Transplant recipients and patients treated chronically with corticosteroids Inconclusive support for any agent Inconclusive support for any agent Inconclusive support for any agent Insufficient
Medications that reduce the risk of fragility fracture in the given patient populations Medications that reduce the risk of fragility fracture in the given patient populations Medications that reduce the risk of fragility fracture in the given patient populations Medications that reduce the risk of fragility fracture in the given patient populations Medications that reduce the risk of fragility fracture in the given patient populations
Postmenopausal women with osteopenia who do not have prevalent vertebral fractures Postmenopausal women with osteopenia who do not have prevalent vertebral fractures Risedronate Risedronate Low to Moderate
Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
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Summary of Benefits Medications

• Alendronate, risedronate, zoledronic acid, and
  denosumab reduce the risk of hip and nonvertebral
  fractures in postmenopausal women with
  osteoporosis.
• Strength of Evidence High
• Bisphosphonates as a class, denosumab,
  teriparatide, and raloxifene reduce the risk of
  vertebral fractures in postmenopausal women with
  osteoporosis.
• Strength of Evidence High
• The combination of alendronate and calcium
  decreased the risk for any type of clinical
  fracture to about one-third that of alendronate
  alone.
• Strength of Evidence Low
• Teriparatide reduces the risk of nonvertebral
  fractures in postmenopausal women with
  osteoporosis.
• Strength of Evidence Moderate
• Reduced risk of other fracture types and risk
  reduction in subpopulations is achieved by fewer
  medications, and the strength of evidence in
  support of the findings is variable.

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
24
Benefits Exercise and Dietary Supplementation (1
of 2)

• The evidence is insufficient to estimate benefits
  from exercise or to identify the duration,
  intensity, or type of exercise program that will
  decrease fracture risk.
• Strength of Evidence Insufficient
• Vitamin D (gt800 units taken orally), taken in
  combination with calcium, may reduce fracture
  risk in people who are institutionalized.
• Strength of Evidence Moderate
• However, evidence is lacking for clear benefit of
  vitamin D when taken alone for the general
  population.

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
25
Benefits Exercise and Dietary Supplementation (2
of 2)

• Studies show no difference between calcium alone
  and placebo in reducing the risk for vertebral
  and nonvertebral fractures.
• Strength of Evidence Moderate
• However, calcium significantly reduced hip
  fracture risk in one pooled analysis and overall
  fracture risk in another pooled analysis.
• There is no difference between calcium alone and
  vitamin D alone in reducing vertebral,
  nonvertebral, or hip fracture risk.
• Strength of Evidence High

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
26
Benefits Menopausal Hormone Therapy

• In studies of postmenopausal women in general,
  MHT reduces the risk of vertebral,
  nonvertebral, and hip fractures.
• Strength of Evidence High
• In postmenopausal women with established
  osteoporosis, MHT does not reduce fracture risk
  significantly.
• Strength of Evidence Moderate
• No differences in comparative effectiveness for
  fracture prevention have been shown between
  bisphosphonates and MHT (estrogen).
• Strength of Evidence Moderate
• No differences in fracture incidence have been
  shown in comparisions of patients treated with
  MHT and either raloxifene or vitamin D.
• Strength of Evidence Low
• The Womens Health Initiative reported serious
  adverse events associated with MHT, such that
  routine use of hormone replacement therapy in
  postmenopausal women is now discouraged.

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
27
Additional Information

• Fracture risk reduction is greatest in women with
  established osteoporosis and/or prevalent
  fractures, and reduction of fracture risk from
  treatment is not dependent on patient age.
• Older individuals (65 years and older) are as
  likely to benefit from treatment as younger
  individuals.
• Strength of Evidence High
• Women with established osteoporosis benefit more
  from treatment than women with osteopenia and
  without prevalent fractures.
• Most authorities no longer consider calcitonin to
  be appropriate treatment for osteoporosis, yet it
  is still widely prescribed. Evidence supports the
  conclusion that it is not effective in
  postmenopausal women with osteoporosis.

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
28
Adverse Effects of Medications for Low Bone
Density or Osteoporosis (1 of 3)
Medication Adverse Effect Magnitude of Association Strength of Evidence
Bisphosphonates Bisphosphonates Bisphosphonates Bisphosphonates
Bisphosphonates (as a class) Possible association with atypical subtrochanteric fractures of the femur Not available, but the risk for this type of fracture is low. (Data are not consistent, but the FDA has issued a boxed warning about this possible adverse effect.) Low
Alendronate Mild upper GI events OR 1.08 95 CI 1.01, 1.15 High
Alendronate Hypocalcemia 9/301 treatment vs. 0/207 placebo Moderate
Zoledronic acid Hypocalcemia OR 7.22 95 CI 1.81, 42.7 Moderate
IV forms of zoledronic acid and ibandronate Osteonecrosis of the jaw Less than one case per 100,000 person-years of exposure. (Nearly all cases of osteonecrosis of the jaw are reported in people being treated for cancer.) High
Mild upper GI events are conditions involving the upper gastrointestinal tract such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn. 95 CI 95 percent confidence interval GI gastrointestinal IV intravenous OR odds ratio (the odds of the condition developing in those taking the listed medications when compared with the odds in patients receiving placebo treatment) Mild upper GI events are conditions involving the upper gastrointestinal tract such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn. 95 CI 95 percent confidence interval GI gastrointestinal IV intravenous OR odds ratio (the odds of the condition developing in those taking the listed medications when compared with the odds in patients receiving placebo treatment) Mild upper GI events are conditions involving the upper gastrointestinal tract such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn. 95 CI 95 percent confidence interval GI gastrointestinal IV intravenous OR odds ratio (the odds of the condition developing in those taking the listed medications when compared with the odds in patients receiving placebo treatment) Mild upper GI events are conditions involving the upper gastrointestinal tract such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn. 95 CI 95 percent confidence interval GI gastrointestinal IV intravenous OR odds ratio (the odds of the condition developing in those taking the listed medications when compared with the odds in patients receiving placebo treatment)
Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
29
Adverse Effects of Medications for Low Bone
Density or Osteoporosis (2 of 3)
Medication Adverse Effect Magnitude of Association Strength of Evidence
Raloxifene Pulmonary embolism OR 5.27 95 CI 1.29, 46.4 High
Raloxifene Thromboembolic events OR 1.63 95 CI 1.36, 1.98 High
Raloxifene Myalgias, cramps, and limb pain OR 1.53 95 CI 1.29, 1.81 High
Raloxifene Hot flashes OR 1.58 95 CI 1.35, 1.84 High
Teriparatide Hypercalcemia OR 12.9 95 CI 10.49, 16.0 Moderate
Teriparatide Headaches OR 1.44 95 CI 1.24, 1.67 Moderate
Denosumab Mild GI events OR 2.13 95 CI 1.11, 4.4 Moderate
Denosumab Rash OR 2.01 95 CI 1.5, 2.73 High
Denosumab Infection OR 1.28 95 CI 1.02, 1.60 High
Mild GI events conditions involving the upper gastrointestinal tract such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn. 95 CI 95 percent confidence interval GI gastrointestinal OR odds ratio (the odds of the condition developing in those taking the listed medications compared with the odds in patients receiving placebo treatment) Mild GI events conditions involving the upper gastrointestinal tract such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn. 95 CI 95 percent confidence interval GI gastrointestinal OR odds ratio (the odds of the condition developing in those taking the listed medications compared with the odds in patients receiving placebo treatment) Mild GI events conditions involving the upper gastrointestinal tract such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn. 95 CI 95 percent confidence interval GI gastrointestinal OR odds ratio (the odds of the condition developing in those taking the listed medications compared with the odds in patients receiving placebo treatment) Mild GI events conditions involving the upper gastrointestinal tract such as acid reflux, esophageal irritation, nausea, vomiting, and heartburn. 95 CI 95 percent confidence interval GI gastrointestinal OR odds ratio (the odds of the condition developing in those taking the listed medications compared with the odds in patients receiving placebo treatment)
Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
30
Adverse Effects of Medications for Low Bone
Density or Osteoporosis (3 of 3)
Medication Adverse Effect Magnitude of Association (From Pooled Analysis of Clinical Data)
Menopausal hormone therapy estrogen alone and estrogen-progestin combination Cerebrovascular accidents Estrogen OR 1.34 95 CI 1.07 to 1.68 Combination OR 1.28 95 CI 1.05 to 1.57 High
Menopausal hormone therapy estrogen alone and estrogen-progestin combination Thromboembolic events Estrogen OR 1.36 95 CI 1.01 to 1.86 Combination OR 2.27 95 CI 1.72 to 3.02 High
Menopausal hormone therapy estrogen alone and estrogen-progestin combination Breast cancer Estrogen In the WHI, associated with reduced incidence of breast cancer in women who have had a hysterectomy when compared with placebo (HR 0.77 95 CI 0.62 to 0.95), but subgroup analysis noted that the risk reduction was concentrated in women without benign breast disease or family history of breast cancer. No risk reduction was seen in women at high risk for breast cancer. Combination In the WHI, associated with more occurrences of invasive breast cancer than with placebo (HR 1.25 95 CI 1.07 to 1.46), tumors more likely to have lymph node metastases (HR 1.78 95 CI 1.23 to 1.58), and more breast cancer-related deaths (HR 1.96 95 CI 1.00 to 4.04).
Anderson GL, Chlebowski RT, Aragaki AK, et al. Lancet Oncol 2012 Mar 6 Epub ahead of print. PMID 22401913. Chlebowski RT, Anderson GL, Gass M, et al WHI Investigators. JAMA 2010 304(15)1684-92. PMID 20959578. 95 CI 95 percent confidence interval HR hazard ratio OR odds ratio WHI Womens Health Initiative Anderson GL, Chlebowski RT, Aragaki AK, et al. Lancet Oncol 2012 Mar 6 Epub ahead of print. PMID 22401913. Chlebowski RT, Anderson GL, Gass M, et al WHI Investigators. JAMA 2010 304(15)1684-92. PMID 20959578. 95 CI 95 percent confidence interval HR hazard ratio OR odds ratio WHI Womens Health Initiative Anderson GL, Chlebowski RT, Aragaki AK, et al. Lancet Oncol 2012 Mar 6 Epub ahead of print. PMID 22401913. Chlebowski RT, Anderson GL, Gass M, et al WHI Investigators. JAMA 2010 304(15)1684-92. PMID 20959578. 95 CI 95 percent confidence interval HR hazard ratio OR odds ratio WHI Womens Health Initiative
Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
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31
Additional Possible Adverse Effects

• These adverse effects are listed by the FDA but
  are not findings of the CER.

Medication Adverse Effect(s) Adverse Effect(s)
Alendronate, Risedronate, and Ibandronate Musculoskeletal pain Hypocalcemia Osteonecrosis of the jaw Severe irritation of upper gastrointestinal mucosa
Zoledronic acid Musculoskeletal pain Renal toxicity and acute renal failure
Denosumab Hypocalcemia Osteonecrosis of the jaw
Teriparatide Increased risk of bone cancer
Vitamin D Signs of toxicity nausea, vomiting, anorexia, polyuria, constipation, weakness, and weight loss
Vitamin D By raising blood levels of calcium, excessive vitamin D can cause dementia, memory loss, and arrhythmias Excess vitamin D can cause irreversible kidney damage and renal failure
Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
32
Treatment Monitoring, Adherence, and Persistence
(1 of 3)

• The evidence to date has not clarified the value
  of BMD monitoring to assess treatment
  effectiveness. According to indirect evidence,
  even patients who continue to lose BMD during
  therapy experience statistically and clinically
  significant reductions in fracture risk.
• Strength of Evidence High
• One large randomized controlled trial (RCT)
  showed that after 5 years of initial alendronate
  therapy, an additional 5 years of therapy
  continued to reduce vertebral fracture risk.
• Continued reduction in nonvertebral fracture risk
  was found at 10 years (in post-hoc analysis) in
• Women who had osteoporosis (T-scores were less
  than -2.5) after 5 years of treatment.
• Women with prevalent vertebral fractures after 5
  years of treatment.
• Strength of Evidence Moderate

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
33
Treatment Monitoring, Adherence, and Persistence
(2 of 3)

• Decreased adherence to bisphosphonates is
  associated with an increased risk of fracture
  (vertebral, nonvertebral, or both).
• Strength of Evidence Moderate
• In general, RCTs examining bisphosphonates report
  high levels of adherence (majority over 90), and
  trials with raloxifene had adherence rates of 65
  to 70 percent.
• Strength of Evidence Moderate
• However, observational studies of patients taking
  bisphosphonates in combination with calcium and
  vitamin D show that adherence and persistence
  with the treatment regimen are poor.
• Strength of Evidence High

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
34
Treatment Monitoring, Adherence, and Persistence
(3 of 3)

• Observational studies show that adherence to
  therapy with bisphosphonates is improved with
  weekly regimens when compared with daily
  regimens.
• Strength of Evidence High
• Evidence is lacking to evaluate comparative
  adherence to monthly versus weekly regimens.
• Observational studies show that other factors
  affecting adherence and persistence include, but
  are not limited to
• Dosing frequency
• Side effects of medications
• Comorbid conditions
• Knowledge about osteoporosis
• Medication cost
• Age, previous history of fracture, and
  concomitant medication use do not appear to
  affect adherence or persistence.
• Strength of Evidence Moderate

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
35
Conclusions (1 of 2)

• The ability of medications to decrease fracture
  risk is most strongly established for
  postmenopausal women with osteoporosis (i.e.,
  bone density scores in the osteoporosis range
  and/or pre-existing fractures).
• Bisphosphonates, denosumab, raloxifene, and
  teriparatide reduce vertebral fracture risk, but
  only alendronate, risedronate, zoledronic acid,
  and denosumab reduce hip fracture risk.
• Raloxifene does not reduce the risk of hip or
  nonvertebral fractures.
• Limited evidence supports a potential benefit for
  vitamin D and calcium (alone or in combination)
  in lowering fracture risk.
• Studies to date are inadequate to provide
  estimates of the benefits or harms of exercise.

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
36
Conclusions (2 of 2)

• Most osteoporosis interventions have notable
  adverse effects that should be taken into account
  in decisionmaking.
• Dosing frequency appears to affect adherence and
  persistence, with weekly doses having improved
  adherence over daily regimens.
• Limited evidence suggests that treatment extended
  beyond 5 years can provide additional reductions
  in vertebral fracture risk (measured at 10
  years). For nonvertebral fractures, post-hoc
  analysis found reduction in risk only for women
  who had osteoporosis or prevalent vertebral
  fractures at five years.
• Monitoring BMD during therapy does not fully
  reflect treatment benefits, as patients with BMD
  losses during antiresorptive therapy may still
  experience reduced fracture risk.

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
37
Gaps in Knowledge (1 of 3)

• Evidence is insufficient to evaluate potential
  associations between bisphosphonate use and
  either esophageal cancer or atrial fibrillation.
  However, an FDA safety review notes that a
  relationship between zoledronic acid and atrial
  fibrillation is still an area of active
  surveillance, though an association is unproven.
• Evidence for the antifracture effects of
  currently available osteoporosis therapies is
  greatest among patients with established
  osteoporosis.
• Studies comparing exercise with medications are
  lacking. Additionally, there are no RCTs
  examining the specific duration, intensity, and
  type of exercise program required to decrease
  fracture risk.

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
38
Gaps in Knowledge (2 of 3)

• Evidence is sparse regarding the effectiveness of
  therapies to prevent or treat osteoporosis in
  men.
• Studies have not directly compared the
  antifracture effectiveness of longer durations of
  therapy among the various medications. Thus, it
  is unclear how long patients should remain on
  therapy. The benefits and harms of drug holidays
  are also unclear.
• Data are insufficient to determine the
  comparative effectiveness among individual
  bisphosphonates or between bisphosphonates and
  calcium, raloxifene, or teriparatide.

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
39
Gaps in Knowledge (3 of 3)

• No RCTs tested combinations of osteoporosis
  therapies or sequential use of osteoporosis
  therapies in relation to fracture outcomes.
• No studies examined explicitly the benefits and
  adverse effects associated with the popular
  practice of BMD monitoring during the course of
  therapy.
• This review did not address quality-of-life
  issues.

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.
40
What To Discuss With Your Patients

• The serious health consequences associated with
  LBD and fracture
• The potential benefits and adverse effects
  associated with LBD treatment options
• The specific instructions for how to take certain
  medicines such as bisphosphonates and the impact
  this might have on the patient's lifestyle
• The importance of adherence and how that affects
  reduction of fracture risk
• Risk factors for LBD and fracture including
  conditions and medications in the elderly that
  might predispose them to falls
• Approaches to avoiding falls such as addressing
  hazards in the home, wearing appropriate
  footwear, and installing night lights
• The specific side effects the patient might
  encounter and when the patient should inform you
  should these occur
• Patient values and preferences regarding
  treatment options

Newberry SJ, Crandall CC, Gellad WG, et al.
Comparative Effectiveness Review No. 53.
Available at www.effectivehealthcare.ahrq.gov/lbd.
cfm.