OSTEOPOROSIS (OP)









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)

  • FRAX tool link. Patients who develop new significant risk factors (e.g. RA, chronic corticosteroid use) after initial screening may need to have their interval shortened. Patients who are receiving OP treatment have different recommendations (see treatment and monitoring below).
  • Reference [15]
Suggested rescreening intervals based on initial BMD and FRAX estimated risk
(For patients who meet criteria in different intervals, use the shortest interval)
Initial BMD 10-year major fracture risk 10-year hip fracture risk Suggested rescreening interval
> -1.0 < 10% < 0.8% > 10 years
-1.0 to -1.4 10 - 14% 0.8 - 1.4% 5 - 10 years
-1.5 to -1.9 15 - 19% 1.5 - 2.2% 3 - 5 years
-2.0 to -2.4 N/A 2.3 - 2.9% < 3 years




  • 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 in 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%
  • One of the most common calcium supplement used. Inexpensive.
  • Calcium carbonate absorption is increased when taken with food and 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. More expensive.
  • Absorption is not affected by food or acid-reducing agents (e.g. H2 blockers, PPIs)
Calcium lactate 13%
  • Often used as a food additive
Calcium gluconate (ex. Cal-Glu®) 9%
  • Typically given intravenously
  • Also available in oral form