Bisphosphonates decrease risk vertebral fracture by approx 50%
Risk of hip fracture decreased by 37%
Estrogen Agonists/Antagonists (Formerly SERMS)
Decreased vertebral fx 30%-55%
60 mg qd
Increase risk DVT
No effect on endometrium
Decreases risk of breast cancer
Causes hot flashes (6%)
Miacalcin: nasal, SQ or IM
200 IU intranasally qd
25-39% reduction vertebral
Possible analgesic action for acute osteoporotic fracture
Forteo 20 ug SQ daily
Previous failed therapy
Decrease vertebral fx 65%
Osteosarcoma in rats
Progesterone combination if no hysterectomy
Risk MI/Stroke/Breast CA
Consider non-estrogen treatment first
Monitor and encourage compliance
Review risk factor modification
Calcium and vitamin D intake
Repeat BMD q 2 years (medicare guidelines)
Osteoporosis in Men
1.5 million men over age 65 in US have osteoporosis
Mortality with hip fractures higher in men up to 37.5%
Absolute BMD in men who fracture hip is higher than in women.
7% white men
5% black men
3% Hispanic men
68 year old WM
Stopped smoking 9 years ago
2 prior pred tapers x 2 weeks
Wt 180 lb, Ht 5 ft 8in
No alcohol, RA
Frequent yard work
ACP Guidelines for Screening in Men Risk Factors
Age >70 years
Low body weight (BMI<20-25 kg/m 2)
Weight loss > 10%
Use of oral corticosteroids
Previous fragility fracture
Ann Intern Med 2008;148:680-684.
Common Secondary Causes in Men
Cushing’s or steroid therapy
Excessive alcohol use
Low calcium intake of Vit D insufficiency
Family history of minimal trauma fracture
Ann Intern Med 2008;148:680-684
ACP Guidelines in Men Recommendations
1- Perform individualized assessment of risk factors for osteoporosis in older men (Strong recommendation; high-quality evidence)
2- Obtain DXA for men who are at increased risk for osteoporosis and are candidates for drug therapy (Strong recommendation; moderate-quality evidence)
3- Further research to evaluate osteoporosis screening tests in men
Ann Intern Med 2008;148:680-684
Treatment in Men
Treat secondary causes
Bisphosphonates reasonable first line
Raloxifene not well studied in men
Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the ACP (Ann Intern Med 2008;149:404-415.)
What are the comparative benefits in fracture reduction among treatments for low bone density?
How does fracture reduction resulting from treatments vary among individuals with different fracture risks?
What are the short and long-term adverse effects and do these vary by specific subpopulations?
Effect of Bisphosphonates on Fracture Risk Reduction Annals 2008;149:404-415 ↓ ↓ ↓ Risedronate ↓ ↓ ↓ Zoledronic acid Not studied ↔ ↓ Ibandronate ↓ ↓ ↓ Alendronate Hip Nonvertebral Vertebral
Copyright restrictions may apply. Black, D. M. et al. JAMA 2006;296:2927-2938. BMD Change in FLEX Participants
Copyright restrictions may apply. Black, D. M. et al. JAMA 2006;296:2927-2938. Incidence of Fracture by Treatment Group
Effect on Fracture Risk Reduction Annals 2008;149:404-415 ↔ Not studied ↔ Tamoxifene ↔ ↔ ↓ Raloxifene modest ↓ modest ↓ modest ↓ Calcium +Vit D Not studied ↓ ↓ Teriparatide ↓ ↓ ↓ Estrogen Not studied ↔ ↓ Calcitonin Hip Nonvertebral Vertebral
MacLean, C. et. al. Ann Intern Med 2008;148:197-213 Risk for hip fractures relative to placebo for participants who are at high risk for fracture, by agent
MacLean, C. et. al. Ann Intern Med 2008;148:197-213 Risk for hip fracture relative to placebo for participants who are not at high risk for fracture, by agent
1- Offer pharmacologic treatment to men and women who have known osteoporosis and to those with h/o fragility fractures. (Strong recommendation; high-quality evidence)
2- Consider treatment for men and women at risk for developing osteoporosis. (weak recommendation; moderate-quality evidence)
3- Choose treatment options based on assessment of risk and benefit to individual patients. (Strong recommendation; moderate-quality evidence)
4- ACP recommends further research to evaluate treatment of osteoporosis in men and women.
Ann Intern Med 2008;149:404-415
Risk of Afib with Bisphosphonates
Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly -Pivotal Fracture Trial (HORIZON)*
RCCT: 7765 postmenopausal women with osteoporosis yearly zoledronic acid vs placebo x 3 yrs.
Significant reduction in hip and vertebral fractures
Increased incidence of Afib classified as serious adverse event ( 1.3% vs 0.4%) P<0.001
Overall freq of AF no different in 2 groups (2.4 vs 1.9%)
Subsequent HORIZON-Recurrent Fracture Trial failed to find increased AF in treatment group.
Rate of AF serious adverse events Horizon-Pivotal Fracture Trial .09% 0.51% Year 3 .17% 0.53% Year 2 .29% 0.47% Year 1 Placebo Zoledronic Acid
Association of other Bisphosphonates with AF Risk
Fracture Intervention Trial (FIT): RCCT of alendronate in 6459 postmenopausal women. Serious adverse AF events alendronate (1.5%) vs placebo (1.0%) P=.07 NEJM 2007;356:1895-1896.
Case control study : More AF patients (719) than controls(966) had ever used alendronate (6.5% vs 4.2%, P=.03) Arch Int Med. 2008;168(8):826-31.
Larger case control study in Denmark : No assn of bisphosphonate use with AF in 13,586 patients w/AF and 68,054 controls. (3.2% vs 2.9%) BMJ 2008;336:813-16.
Some suggestion of increased AF serious adverse events with bisphosphonate therapy
Not a consistent finding
Prior RCCT were not designed to examine the occurrence of Afib.
Unlikely that there is causal relation between AF and bisphosphonates.
68 year old WF calls you saying that her dentist wants to extract a tooth, but he is very concerned because she is on alendronate 70mg weekly. She wants to know your opinion regarding her risk for ONJ.
PMH: 2 prior fragility fractures, T score <2.5
MEDS: alendronate 70 mg x 8 years
Bisphosphonate Associated ONJ: Definition
Current or previous treatment with a bisphosphonate
Exposed, necrotic bone in the maxillofacial region > 8 weeks
No history of radiation therapy to the jaws
American Academy of Oral and Maxillofacial Surgeons
Case Series 119 patients . J Oral Maxillofac Surg. 2005 Nov;63(11):1567-75
Case Series 119 patients J Oral Maxillofac Surg. 2005 Nov;63(11):1567-75
Annals systematic review: 368 ONJ patients
84% with multiple myeloma or breast cancer
4% with osteoporosis
60% after dentoalveolar surgery
Remaining 40% probably related to infection, denture trauma or other trauma
Prevalence of ONJ in cancer patients 6-10%
Prevalence in osteoporosis patients unknown
Ann Intern Med 2006;144:753-761.
ASBMR task force review of case reports estimated risk as 1 in 10,000 to 1 in 100,000 patient years of treatment.
Merk: 170 cases/20 million patient years (0.7/100,000patient years)
Proctor and Gamble: 1/10,000 patient years
No cases of ONJ reported alendronate, risedronate, ibandronate
HORIZON: 2 cases (control, and placebo equal)
Population based prevalence studies :
3 cases in 780,000 patients receiving bisphosphonates for osteoporosis.
<1 in 100,000 patient-years
Patient later informed you that she underwent procedure without incident. The dentist had drawn “blood-work” which indicated that her risk for ONJ was very low.
Bone Turnover Markers as Predictors of Risk?
Serum levels of morning fasting C terminal telopeptide (CTX)
Based on data from 17 ONJ patients receiving bisphosphonates
<100 low risk
100-150 moderate risk
>150 high risk
Reduced markers of resorption expected in patients receiving bisphosphonates
Low normal range in healthy women falls within range proposed as high risk.
J Oral Maxillofac Surgery 2007;65:2397-2410
Risk of ONJ <1 in 100,00 patient years in non-cancer patients using bisphosphonate treatment suggests a positive benefit-risk profile.
All patients taking bisphosphonates should be informed of the benefits and risks of treatment.
Patients taking bisphosphonates should be encouraged to maintain good oral hygeine.
Consider screening postmenopausal women and men over 50 at increased risk for osteoporosis
Educate patients on universal recommendations
Consider treating patients with:
Prior fragility fracture
Osteopenic patients with elevated risk profile
Review risk/benefit profile with all patients
Medicare Coverage for BMD Testing
Estrogen deficient women at clinical risk
Individuals with vertebral abnormalities
Individuals receiving or planning to receive long term glucocorticoid therapy
To assess response to therapy
Screening: Pros and Cons
Common disease with significant morbidity
Screening methods available
Interventions available to reduce risk
Knowledge of risk could improve compliance
Little direct evidence that screening improves outcome.
No cutoff value for BMD that delineates fracture risk.
Other risk factors may be more important than BMD
Cost efficiency issues
Knowledge of normal value may hinder compliance
Non-FDA Approved Drugs
Other bisphosphonates: (etidronate, pamidronate, tiludronate)
Parathyroid Hormone (PTH-84)
Adverse Effects of Drugs
Mild upper GI events (reflux, nausea)
Osteonecrosis of the jaw:
Alendronate and zolendronic acid
Breast cancer (estrogen + progesterone)
RCCTS no evidence of serious adverse events
Calcium and vitamin D
RCCTs no clinically important serious adverse events.