OSTEOPOROSIS (OP)

• ACRONYMS AND DEFINITIONS

• ACP - American College of Physicians
• ACR - American College of Rheumatology
• AACE - American Association of Clinical Endocrinologists
• BMD - Bone mineral density
• DXA - Dual-energy x-ray absorptiometry
• FRAX - Fracture risk assessment tool
• GC - Glucocorticoids
• IOF - International Osteoporosis Foundation
• NAM - National Academy of Medicine
• USPSTF - U.S. Preventive Services Task Force
• VTE - Venous thromboembolism

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• PATHOPHYSIOLOGY

• Overview
• Osteoporosis is a bone disorder marked by decreased bone strength and an increased risk of fracture
• Osteoporosis generally occurs because of an imbalance in bone remodeling
• Mature adult bones continually undergo a process of bone remodeling where old bone is replaced with new bone
• Bone remodeling is governed by two types of cells:
• Osteoblasts - cells that produce new bone
• Osteoclasts - cells that resorb old bone
• Osteoblast and osteoclast activity is modulated by a number of hormones and cytokines. Imbalances in these modulators can lead to inefficient remodeling, excessive osteoclast activity, and eventually, osteoporosis.
• A protein called receptor activator of nuclear factor-κβ ligand (RANKL) has been found to play a pivotal role in stimulating osteoclast activity. RANKL production is increased by the hormonal changes seen in menopause. It is inhibited by a protein called osteoprotegerin (OPG). The osteoporosis drug denosumab binds RANKL and inactivates it.
• Other hormones and cytokines play a role in bone remodeling, and in many cases, their specific role has not been fully elucidated [1]



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• RISK FACTORS

• Overview
• A long list of conditions have been associated with osteoporosis in observational trials. Confounding is likely an issue in many of these studies.
• The table below lists risk factors for osteoporosis that have been largely validated and are included in the FRAX tool

• 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	See rheumatoid arthritis for more
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

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• OSTEOPENIA

• Osteopenia is a milder form of bone loss than osteoporosis. In DXA scanning, osteopenia is defined as a T-score between -1.0 and -2.5.
• The risk of fracture varies widely in patients with osteopenia. In general, fracture risk is less than that of osteoporosis, but still significant with about half of fractures attributable to weak bones occurring in patients with osteopenia. [1]
• The risks and benefits of pharmacological treatment in patients with osteopenia has not been studied extensively. One large study published in 2018 found that zoledronic acid for 6 years reduced the incidence of fractures in women with osteopenia. Subjects in the study had a median 10-year risk of hip fracture and osteoporosis-related fracture of 2.4% and 12%, respectively. That study is detailed here - zoledronic acid vs placebo in osteopenia.
• Current guidelines recommend treating patients with osteopenia who are at increased risk of fracture. Increased risk is defined as a 10-year risk of ≥ 3% for a hip fracture or ≥ 20% for major osteoporosis-related fracture based on the FRAX tool

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• SCREENING

• 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

• Rescreening
• Professional guidelines do not offer guidance on rescreening patients for osteoporosis
• A cohort study published in the NEJM in 2012 looked at the risk of osteoporosis in postmenopausal women ≥ 65 years of age based on their initial T-scores. Findings from that study are presented in the table below. A review article published in the JAMA in 2021 used data from that study and others to suggest on appropriate rescreening intervals based on initial T-scores and FRAX-calculated risk estimates. The second table shows those recommendations.

• 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)

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• DIAGNOSIS

• DXA scanning
• DXA stands for dual-energy x-ray absorptiometry. DXA is an imaging technique where X-rays are aimed at a person's bones. The absorption of the X-ray beams by the bone is measured, and from this, bone mineral density (BMD) can be estimated.
• The hips and lumbar spine are the most accurate areas for assessing BMD
• BMD units are reported as grams of mineral per cm². They are also expressed as T-scores and Z-scores. The T-score represents the number of standard deviations that the person's BMD deviates from that of a healthy young adult. The Z-score represents the number of standard deviations that a person's BMD deviates from an age-, race- and sex-matched control.
• T-scores are used for diagnosis and treatment decisions in most cases. In premenopausal women, men < 50 years of age, and children, T-scores have not been validated, and Z-scores should be used. In these patients, the International Society for Clinical Densitometry (ISCD) recommends that a Z-score ≤ -2.0 be used to define low BMD. [1,2]
• T-score and Z-score definitions are presented in the table below

• 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

• X-ray
• Vertebral fractures are considered diagnostic for osteoporosis, and they are also an indication for pharmacological treatment
• Most vertebral fractures are asymptomatic and go undiagnosed
• Vertebral fractures can be diagnosed with lateral X-rays of the thoracic and lumbar spine. Many DXA machines can also assess for vertebral fractures using a technology called lateral vertebral fracture assessment (VFA). [2]
• The International Osteoporosis Foundation recommends vertebral imaging be considered in the following patients:
• All women age 70 and older and all men age 80 and older if BMD T-score at the spine, total hip, or femoral neck is ≤ −1.0
• Women age 65 to 69 and men age 70 to 79 if BMD T-score at the spine, total hip, or femoral neck is ≤ −1.5
• Postmenopausal women and men age 50 and older with any of the following risk factors:
• Low-trauma fracture during adulthood (age 50 and older)
• Historical height loss of 1.5 inches (4 cm) or more
• Prospective height loss of 0.8 inch (2 cm) or more
• Recent or ongoing long-term glucocorticoid treatment [2]

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• SECONDARY CAUSES

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• TREATMENT AND MONITORING

• 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

• Reference [13,16]

ACP 2023 Osteoporosis Treatment Recommendations for Women and Men
WHOM TO TREAT
Men and postmenopausal women with primary osteoporosis defined as: Osteoporosis that is not secondary to a separate condition (e.g. cancer) or medications (e.g. glucocorticoids) A BMD value at the femoral neck, the lumbar spine, or both that is ≥ 2.5 standard deviations below the mean BMD value for a young woman; osteoporosis may be diagnosed in postmenopausal women and men aged ≥ 50 years if the T-score for the lumbar spine, total hip, or femoral neck is 2.5 or less (in certain circumstances, the 33% radius [also called the 1/3 radius] may be used)
CHOICE OF THERAPY
First line (women and men) Alendronate (Fosamax®) Ibandronate (Boniva®) Risedronate (Actonel®) Zoledronic acid (Reclast®) Second line (women and men) Denosumab (Prolia®) is recommended in patients who have contraindications to or experience adverse effects of bisphosphonates Females with osteoporosis and very high fracture risk Romosozumab (Evenity®) or Teriparatide (Forteo®) followed by a bisphosphonate Very high fracture risk may include the following: Older age Recent fracture (within 12 months) History of multiple osteoporotic fractures Multiple risk factors for fracture (e.g. rheumatoid arthritis, smoking, low body weight, white, hyperkyphosis, falls) Females > 65 years with osteopenia Clinicians should take an individualized approach regarding whether to start pharmacologic treatment with a bisphosphonate Clinical considerations Adequate calcium and vitamin D intake, exercise, and fall prevention should be a part of all regimens Females initially treated with an anabolic agent (abaloparatide, teriparatide, romosozumab) should be offered an antiresorptive agent after discontinuation to preserve gains and because of serious risk for rebound and multiple vertebral fractures
THERAPY MONITORING AND DURATION
Treat women with osteoporosis with pharmacologic therapy for 5 years Do not perform BMD testing during the 5-year treatment period The decision of a temporary treatment discontinuation (holidays) should be individualized and based on baseline risk for fractures, type of medication and its half-life in bone, duration of discontinuation, benefits and harms of discontinuation, and higher risk for fracture due to drug discontinuation

• Reference [4]

Endocrine Society 2012 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.

• Glucocorticoid-induced osteoporosis
• During the first 3 months of glucocorticoid therapy, a rapid decline in bone mineral density is often seen. The decline peaks around 6 months and then continues at a slower pace with continued use. Doses of prednisolone or equivalent as low as 2.5 mg/day have been associated with increased fracture risk in some studies, while others have found no increased risk with doses under 5 mg/day. [7]
• Recommendations from the American College of Rheumatology for the treatment and prevention of glucocorticoid-induced osteoporosis are presented below

• 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)

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• VITAMIN D

• Vitamin D plays an important role in calcium regulation and bone health. See the links below for information on vitamin D.
• Recommended dietary allowance for vitamin D
• Vitamin D supplements
• Vitamin D serum levels
• Vitamin D in calcium regulation

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• CALCIUM

• Physiology
• Calcium and phosphate combine to form hydroxyapatite, the mineral that gives bone strength. Ninety-nine percent of body calcium is found in bones and 1% is in the extracellular space. Extracellular calcium plays an important role in nerve conduction and muscle contraction so serum levels are tightly regulated (see calcium regulation). When dietary calcium is inadequate to maintain proper serum calcium levels, calcium is mobilized from bone through bone resorption. Chronic bone resorption can lead to decreased bone density and fractures. [1]

• 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)

• Calcium supplements
• Patients who may have a dietary deficiency of calcium may take supplements so that they meet their recommended dietary intake
• It's important to note that there is no conclusive evidence that calcium supplementation prevents fractures or has a significant effect on BMD [10,11]
• Calcium supplements are detailed in the table below. Calcium carbonate and calcium citrate are the most commonly used supplements.

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• BIBLIOGRAPHY

• 1 - PMID 21224201 AACE OP GL
• 2 - PMID 25182228 IOF GL
• 3 - USPSTF website
• 4 - PMID 22675062 Endocrine society recs in men
• 5 - PMID 21083387 Bisphosphonates for OP
• 6 - PMID 21542743 Femoral fx risk
• 7 - PMID 20662044 ACR recs
• 8 - PMID 16837676 Ruth trial
• 9 - PMID 25423325 Ospemifene MOA
• 10 - PMID 26420598 - Calcium intake and BMD
• 11 - PMID 26420387 - Calcium intake and fracture risk
• 12 - PMID 28585410 - 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis
• 13 - PMID 28492856 - Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update From the American College of Physicians, Annals of Internal Medicine (2017)
• 14 - PMID 30907953 - Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab (2019)
• 15 - PMID 34698797 - Serial Bone Density Measurement for Osteoporosis Screening, JAMA (2021)
• 16 - PMID 36592456 - Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass to Prevent Fractures in Adults: A Living Clinical Guideline From the American College of Physicians, Ann Intern Med (2023)