OSTEOPOROSIS









illustration of bone remodeling and the action of osteoporosis drugs



  • Reference [1,2]
Risk factors for osteoporosis included in the FRAX tool
Risk factor Comment
Age
  • Age-related bone loss occurs after age 60 in women and men
  • Occurs at a rate of 0.5% per year
Female
(Menopause)
  • There is accelerated bone loss during the menopause transition
  • Bone loss up to 10% may occur in some women
Low BMI (< 20)
  • See BMI for more
Previous fracture
  • A previous fracture in adult life occurring spontaneously, or a fracture arising from trauma which, in a healthy individual, would not have resulted in a fracture
Parental hip fracture
  • History of a hip fracture in mother or father
Oral corticosteroids
  • In patients who ever received ≥ 5 mg/day of prednisone or equivalent for > 3 months
Current smoking
Alcohol intake
  • ≥ 3 drinks a day
Rheumatoid arthritis
Chronic diseases
(secondary osteoporosis)
  • Osteogenesis imperfecta
  • Hyperthyroidism (if untreated and long-standing)
  • Hypogonadism and premature menopause (< 45 years)
  • Chronic malnutrition and malabsorption (e.g. celiac, short bowel syndrome)
  • Chronic liver disease






  • Reference [3,4]
USPSTF osteoporosis screening recommendations
Women
  • ≥ 65 years: screen all women
  • Postmenopausal women < 65 years: screen women who are at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool. The USPSTF recommendations do not provide specific guidance on the degree of increased risk that warrants testing. They provide an example that says if a woman's 10-year risk of major osteoporotic fracture is greater than that of an average-risk 65 year-old woman, then testing is justified. In the U.S., the 10-year fracture risk of an average-risk 65 year-old woman is 8.4% using the FRAX tool.
  • The preferred screening method is DXA scanning
Men
  • Insufficient evidence to recommend screening
Endocrine Society osteoporosis screening recommendations in men
Men
  • ≥ 70 years: screen all men
  • 50 - 69 years: screen if any of the following risk factors are present:
    • History of fracture after age 50
    • Delayed puberty
    • Hypogonadism
    • Hyperparathyroidism
    • Hyperthyroidism
    • COPD
    • Corticosteroid use
    • GnRH agonists use
    • Alcohol abuse or smoking
    • Other causes of secondary osteoporosis (ex. rheumatoid arthritis)
  • The preferred screening method is DXA scanning


  • Intervals are from adjusted analysis
  • Reference [7]
Estimated time interval for at least 10% of women in each group to transition to osteoporosis on BMD testing
Initial BMD Interval (95% CI)
Normal
(T-score -1.0 or higher)
16.8 years (11.5–24.6)
Mild osteopenia
(T-score -1.01 to -1.49)
17.3 years (13.9 – 21.5)
Moderate osteopenia
(T-score -1.50 to -1.99)
4.7 years (4.2 – 5.2)
Advanced osteopenia
(T-score -2.0 to -2.49)
1.1 years (1.0 – 1.3)




  • Reference [1,2]
Classification criteria for BMD T-scores
Category T-score
Normal -1 or above
Osteopenia -1.0 to -2.5
Osteoporosis -2.5 or below

  • Z-scores are recommended in premenopausal women, men < 50 years of age, and children
  • Reference [2]
Classification criteria for Z-scores
Category Z-score
Within expected range greater than -2.0
Below expected range for age -2.0 and below




  • Reference [1,2]
Medical conditions associated with osteoporosis
Condition Comment
Hyperparathyroidism
  • May be primary or secondary
  • Marked by elevated calcium and PTH levels
Cushing's syndrome
Gastrointestinal disorders
  • Celiac disease, inflammatory bowel disease, gastric bypass, etc.
  • Decreased calcium and vitamin D absorption
Hyperthyroidism
  • Check TSH
End-stage kidney disease
  • Decreased phosphate excretion and decreased vitamin D conversion by the kidneys leads to hypocalcemia and elevated PTH levels
Hyperprolactinemia
  • Causes hypogonadal state that leads to bone loss
Hemochromatosis
  • Iron deposition in pituitary cells leads to secondary hypogonadism
  • Check ferritin level
Athletic amenorrhea
  • Marked by excessive exercise, low calorie intake, menstrual dysfunction, and low bone mass
Monoclonal gammopathies
  • Marked by osteolytic bone lesions and hypercalcemia
  • Check serum and urine protein electrophoresis/immunofixation

  • Reference [1,2]
Medications associated with osteoporosis
Medication Comment
Anticonvulsants
  • Specifically carbamazepine, phenobarbital, phenytoin, and primidone
  • Drugs decrease levels of vitamin D through enzyme induction
Aromatase inhibitors
  • Block estrogen synthesis
  • Used to treat and prevent breast cancer
  • Drugs include Anastrozole (Arimidex®) and Exemestane (Aromasin®)
Depo Provera®
  • Popular birth control method
  • Suppresses estrogen levels
Glucocorticoids
Lithium
  • Lithium may raise parathyroid levels leading to bone mineral loss
SGLT2 inhibitors
  • Medications include Invokana®, canagliflozin, Farxiga® etc.
  • SGLT2 inhibitors, particularly canagliflozin, have been shown to decrease BMD and increase fracture risk
Proton pump inhibitors
  • Medications include Prevacid®, Nexium®, Prilosec®, etc.
  • In observational studies, long-term (> 1 year) PPI use has been associated with an increased risk of fracture
  • Calcium absorption is affected by acid-reducing agents
Glitazones
  • Actos® and Avandia®
  • Glitazones have been associated with an increased risk of fractures
  • See glitazones and fractures for more
Thyroid hormone replacement
  • Excessive thyroid hormone replacement can cause osteoporosis
  • See hypothyroidism for more
Immunomodulators
  • Methotrexate, cyclosporine, tacrolimus, etc.
GnRH agonists
  • Leuprolide (Lupron®), Goserelin (Zoladex®), etc.
  • Used to treat prostate cancer and endometriosis
  • GnRH agonists overstimulate the pituitary and cause it to stop releasing FSH and LH. This causes a hypogonadal state.



  • Reference [14]
Endocrine Society 2019 Osteoporosis Treatment Recommendations for Postmenopausal Women
WHOM TO TREAT
Step 1 - Determine patient's fracture risk
  • Risk categories are determined using the FRAX tool and should include BMD total hip or femoral measurements

Step 2 - Assign risk category below
  • Low risk - no prior hip or spine fractures, a BMD T-score at the hip and spine both above -1.0, and 10-year hip fracture risk < 3% and 10-year risk of major osteoporotic fractures < 20%
  • Moderate risk - includes no prior hip or spine fractures, a BMD T-score at the hip and spine both above -2.5, or 10-year hip fracture risk < 3% or risk of major osteoporotic fractures < 20%
  • High risk - includes a prior spine or hip fracture, or a BMD T-score at the hip or spine of -2.5 or below, or 10-year hip fracture risk ≥ 3%, or risk of major osteoporotic fracture risk ≥ 20%
  • Very high risk - includes multiple spine fractures and a BMD T-score at the hip or spine of -2.5 or below
CHOICE OF THERAPY
Low risk
  • No treatment and reassess fracture risk in 2 - 4 years.
Moderate risk
  • No treatment and reassess fracture risk in 2 - 4 years OR treat with bisphosphonate
High risk or Very high risk
  • Treat with one of the following:
    • Bisphosphonate
    • Denosumab
    • Teriparatide or abaloparatide

Patients who cannot tolerate the above recommended therapies
  • Age > 60 years, one of the following (in order of preference)
    • 1. SERM
    • 2. Hormone replacement therapy
    • 3. Calcitonin
    • 4. Calcium + Vitamin D
  • Age < 60 OR < 10 years past menopause (low VTE risk)
    • No vasomotor symptoms OR high breast cancer risk: SERM
    • Vasomotor symptoms: Hormone replacement therapy
MONITORING THERAPY
Oral bisphosphonate
  • Reassess fracture risk in 5 years
Intravenous bisphosphonate
  • Reassess fracture risk on 3 years
Denosumab
  • Reassess fracture risk in 5 - 10 years
Teriparatide or abaloparatide
  • After 2 years of therapy, switch patient to bisphosphonate or denosumab
DURATION OF THERAPY
Bisphosphonate
  • On reassessment, patient at low or moderate risk
    • Consider a drug holiday (discontinuation for up to 5 years or longer if appropriate)
    • Reassess fracture risk every 2 - 4 years
    • If bone loss occurs or patient becomes high risk, consider restarting therapy
  • On reassessment, patient at high risk
    • Continue therapy or switch to another therapy
Denosumab
  • On reassessment, patient at low or moderate risk
    • Consider giving bisphosphonate and then stopping for a drug holiday (discontinuation for up to 5 years or longer if appropriate)
    • Reassess fracture risk every 1 - 3 years
    • If bone loss, fracture occurs, or patient becomes high risk, consider restarting therapy
  • On reassessment, patient at high risk
    • Continue therapy or switch to another therapy
  • **High risk is not clearly defined. In general, patients who meet the criteria for initiating therapy are considered high risk.
  • A - International Osteoporosis Foundation recommendation
  • B - Amer Assoc of Clinical Endocrinologists recommendation
  • C - American College of Physicians recommendation
  • Reference [1,2,13]
IOS / AACE / ACP Osteoporosis Treatment Recommendations for Women
WHOM TO TREAT
Pharmacological treatment is recommended in postmenopausal women ≥ 50 years with any of the following:
  • History of hip or spine fracture (clinical or subclinical)
  • T-score of -2.5 or less at the spine, femoral neck, or total hip
  • T-score between -1.0 and -2.5 with a 10-year risk of ≥ 3% for a hip fracture or ≥ 20% for major osteoporosis-related fracture based on the FRAX tool [A,B]
CHOICE OF THERAPY
First line
  • Alendronate (Fosamax®)
  • Risedronate (Actonel®)
  • Zoledronic acid (Reclast®)
  • Denosumab (Prolia®) [B,C]
Second line
  • Ibandronate
  • Raloxifene (Evista®)
Third line
  • Calcitonin (Miacalcin®)
Other
  • Consider teriparatide (Forteo®) in patients at very high risk of fracture and in those who failed bisphosphonate therapy
  • Combination therapy is not recommended [B]
The ACP recommends against using menopausal estrogen therapy or menopausal estrogen plus progestin therapy or raloxifene for the treatment of osteoporosis in women
MONITORING THERAPY
  • BMD testing with DXA scan every 2 years is recommended by the IOF [A]
  • The ACP 2017 OP guidelines recommend against BMD testing during the 5-year pharmacologic treatment period [C]
DURATION OF THERAPY
IOF recommendation
  • No pharmacologic therapy should be considered indefinite in duration
  • Bisphosphonates may have residual effects even after treatment discontinuation
  • After 3 - 5 years of therapy with bisphosphonates, reassess fracture risk with history, DXA scanning, and vertebral imaging if indicated
  • It is reasonable to discontinue bisphosphonates after 3 to 5 years in patients who appear to be at modest risk of fracture
  • In patients who are at high risk**, therapy should be continued [A]
ACP recommendation
  • Treat women with OP with pharmacologic therapy for 5 years. Do not perform BMD testing during the 5-year treatment period. [C]

  • Reference [4]
Endocrine Society Osteoporosis Treatment Recommendations for Men
WHOM TO TREAT
Treat men with any of the following
  • Men who have had a hip or vertebral fracture without major trauma
  • Men who have not experienced a spine or hip fracture but whose BMD of the spine, femoral neck, and/or total hip is ≥ 2.5 standard deviations below the mean of normal young white males
  • In the U.S., men who have a T-score between –1.0 and –2.5 in the spine, femoral neck, or total hip plus a 10-yr risk of experiencing any fracture ≥ 20% or 10-yr risk of hip fracture ≥ 3% using FRAX; further studies will be needed to determine appropriate intervention levels using other fracture risk assessment algorithms. For men outside the U.S., region-specific guidelines should be consulted.
  • Men who are receiving long-term glucocorticoid therapy in pharmacological doses (e.g. prednisone or equivalent > 7.5 mg/d), according to the 2010 guidelines of the American Society of Rheumatology. See also glucocorticoid-induced osteoporosis below.
CHOICE OF THERAPY
One of the following
  • Alendronate (Fosamax®)
  • Risedronate (Actonel®)
  • Zoledronic acid (Reclast®)
  • Teriparatide (Forteo®)
Men receiving androgen-deprivation therapy for prostate cancer
  • Denosumab (Prolia®)
Men with recent hip fracture
  • Zoledronic acid (Reclast®)
Men with testosterone < 200 ng/dl
  • Testosterone replacement therapy may be considered instead of standard therapies if symptoms of hypogonadism are present or if other therapies are not appropriate
MONITORING THERAPY
  • Check BMD by DXA every 1 - 2 years. If BMD reaches a plateau, less frequent measurements may be appropriate.


  • Reference [12]
ACR 2017 Recommendations for Glucocorticoid-induced Osteoporosis
WHOM TO SCREEN
Patients receiving long-term glucocorticoids defined as ≥ 2.5 mg/day for ≥ 3 months
  • Adults < 40 years old
    • History of OP fracture OR any of the following: malnutrition, significant weight loss or low body weight, hypogonadism, secondary hyperparathyroidism, thyroid disease, family history of hip fracture, history of alcohol use ( ≥ 3 units/day) or smoking
      • BMD test within 6 months of starting GCs
    • No risk factors
      • No BMD testing
  • Adults ≥ 40 years old
    • FRAX with GC-dose correction and BMD testing within 6 months of starting GC treatment. For GC-dose correction, increase the risk generated with FRAX by 1.15 for major osteoporotic fracture and 1.2 for hip fracture

Follow-up testing
  • In general, the recommendations state that patients with any risk factor for OP should have BMD testing every 2 - 3 years
WHOM TO TREAT
Adults < 40 years old
  • Treat if any of the following are present:
    • History of osteoporosis fracture
    • Z score < -3 at hip or spine and prednisone ≥ 7.5 mg/day
    • Greater than 10%/year loss of BMD at hip or spine and prednisone ≥ 7.5 mg/day
    • Very high dose GC (prednisone ≥ 30 mg/day and cumulative dose of > 5 grams) and ≥ 30 years old

Adults ≥ 40 years old
  • Treat if any of the following are present:
    • History of osteoporosis fracture
    • Men ≥ 50 years and postmenopausal women with a T-score ≤ -2.5 at the hip or spine
    • GC-adjusted FRAX 10-year risk for major osteoporotic fracture ≥ 10%
    • GC-adjusted FRAX 10-year risk for hip fracture > 1%
    • Very high dose GC (prednisone ≥ 30 mg/day and cumulative dose of > 5 grams)

  • For GC-adjusted FRAX, increase the risk generated with FRAX by 1.15 for major osteoporotic fracture and 1.2 for hip fracture
CHOICE OF THERAPY
Women of childbearing potential
  • Oral bisphosphonate (first-line)
  • Teriparatide (second-line)
  • All patients should receive calcium 1000 - 1200 mg/day and vitamin D 600 - 800 IU/day (maintain serum level ≥ 20 ng/ml)

Women not of childbearing potential and men
  • Oral bisphosphonate (first-line)
  • IV bisphosphonates (second-line)
  • Teriparatide (third-line)
  • Denosumab (fourth-line)
  • All patients should receive calcium 1000 - 1200 mg/day and vitamin D 600 - 800 IU/day (maintain serum level ≥ 20 ng/ml)







  • Reference [1]
NAM recommended daily dietary allowance for calcium
Age Sex Calcium (elemental)
0 - 6 months M/F 200 mg
7 - 12 months M/F 260 mg
1 - 3 years M/F 700 mg
4 - 8 years M/F 1000 mg
9 - 18 years M/F 1300 mg
19 - 50 years M/F 1000 mg
51 - 70 years M 1000 mg
51 - 70 years F 1200 mg
≥ 71 years M/F 1200 mg

  • Reference [2]
Calcium content of dairy products
Food Calcium (mg)
Milk (8 oz) 300 mg
Yogurt (6 oz) 300 mg
Cheese (1 oz or cubic in.) 200 mg
Fortified foods 80 - 1000 mg (varies widely)

  • For doses > 500 mg/day, give in divided doses to improve absorption
  • Reference [2]
Calcium supplement % elemental calcium Other
Calcium carbonate (ex. Caltrate®) 40%
  • Cheap. One of the most common calcium supplements used.
  • Calcium carbonate relies on stomach acid for absorption so its absorption is increased when taken with food. Absorption is decreased by acid-reducing agents (e.g. H2 blockers, PPIs)
  • Also used to treat hyperphosphatemia in chronic kidney disease
Calcium acetate 25%
Calcium citrate (ex. Citracal®) 21%
  • One of the most common calcium supplements used
  • Absorption is not affected by food, and acid-reducing agents (e.g. H2 blockers, PPIs) do not decrease absorption
Calcium lactate 13%
  • Often used as a food additive
Calcium gluconate (ex. Cal-Glu®) 9%
  • Typically given intravenously
  • Also available in oral form