OSTEOPOROSIS (OP)

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• Overview
• Osteoporosis is a bone disorder marked by decreased bone strength and increased fracture risk. Adult bone continually undergoes remodeling, where old bone is replaced with new bone. Bone remodeling is performed by two types of cells: osteoblasts, which produce new bone, and osteoclasts, which resorb old bone. The activity of these cells is controlled by hormones and cytokines, and imbalances in these regulators can lead to bone weakness and fractures.
• One protein that plays a pivotal role in stimulating osteoclast activity is receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL production is inhibited by estrogen. After menopause, RANKL activity increases, and it plays an important role in menopausal osteoporosis. The osteoporosis drug denosumab binds RANKL and inactivates it. [1]



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• Age (most common) - age-related bone loss occurs after age 60 in both sexes
• Menopause
• Low BMI (< 20)
• Previous fracture - 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
• Hip fracture in mother or father
• Oral corticosteroids at a dose of ≥ 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

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• The three tools below are used to assess osteoporosis and fracture risk


• Fracture Risk Assessment Tool (FRAX) tool - most widely used tool; predicts 10-year risk of fracture based on 11 risk factors; risk can be calculated with or without BMD data


• Osteoporosis Risk Assessment Instrument (ORAI) - primary use is to identify women younger than 65 who may be at increased risk of osteoporosis; incorporates age, weight, and current estrogen use to predict risk


• Osteoporosis Self Assessment Tool (OST) - primary use is to identify men and postmenopausal women younger than 65 who may be at increased risk of osteoporosis; incorporates age, sex, and weight to predict risk

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• Osteopenia is a milder form of bone loss defined as a T-score between -1.0 and -2.5 (see DXA scanning). Although fracture risk varies widely in patients with osteopenia, it is still significant. [1]
• The risks and benefits of treating osteopenia have not been studied extensively. A large 2018 study found that six years of zoledronic acid reduced fracture incidence in women with osteopenia. Subjects in the study had a median 10-year risk of hip and osteoporosis-related fractures of 2.4% and 12%, respectively (see zoledronic acid vs placebo in osteopenia). Current guidelines recommend treating patients with osteopenia who have a 10-year risk of hip or major osteoporosis-related fracture that is ≥3% or ≥20%, respectively (see FRAX tool).

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• Reference [3,4]

USPSTF osteoporosis screening recommendations
Women Women 65 years an older: screen all women Postmenopausal women younger than 65 years with one or more risk factors for osteoporosis: screen women who are at increased risk for an osteoporotic fracture as estimated by clinical risk assessment. The guidelines recommend a two-step approach. First, assess women for the following: low body weight, parental history of hip fracture, cigarette smoking, excess alcohol consumption. If one or more is present, use a risk assessment tool to identify women at increased risk. For the FRAX tool, the USPSTF does not give a specific threshold for increased risk but provides the following for context: a 65-year-old White female with a BMI of 25 and no risk factors has a 10-year risk of hip fracture of 1.3% and a 10-year risk of major osteoporotic fracture of 9.3% 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 make recommendations on when to rescreen patients for osteoporosis. Results from a cohort study evaluating the risk of osteoporosis in women ≥ 65 based on their initial T-scores are presented in the table below. A 2021 review article used data from that study and others to suggest appropriate rescreening intervals based on initial T-scores and FRAX-calculated risk estimates. Those recommendations are presented in the second table.

• 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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• DXA scanning
• Dual-energy x-ray absorptiometry (DXA) is an imaging technique that estimates bone mineral density (BMD) based on the absorption of X-ray beams by different areas of the skeleton. The hip bones and lumbar spine are the most accurate areas for assessing BMD, which is reported as grams of mineral per cm². The T-score, which represents the number of standard deviations the BMD deviates from that of a healthy young adult, is used to categorize findings into normal, osteopenia, and osteoporosis. Another metric called the Z-score is also given. It represents the number of standard deviations the BMD deviates from age-, race- and sex-matched controls.
• T-scores are typically used for diagnostic and treatment decisions. However, in premenopausal women, men younger than 50, and children, T-scores have not been validated, and Z-scores should be used. In these cases, the International Society for Clinical Densitometry (ISCD) recommends using a Z-score of -2.0 or less to define low BMD. T-score and Z-score classifications are provided in the table below. [1,2]

• Reference [1,2]

T-score
Category	T-score
Normal	-1 or above
Osteopenia	-1.0 to -2.5
Osteoporosis	-2.5 or below
Z-score
Category	Z-score
Within expected range	greater than -2.0
Below expected range for age	-2.0 and below

• X-ray
• Vertebral fractures, which are typically asymptomatic, are considered diagnostic for osteoporosis and are an indication for pharmacological treatment. They can be seen with lateral X-rays of the thoracic and lumbar spine and are also detectable by DXA machines that use lateral vertebral fracture assessment (VFA) technology. The IOF recommends vertebral imaging be considered in the following patients:
• All women 70 and older and all men 80 and older with T-scores at the spine, total hip, or femoral neck of −1.0 or less
• Women 65 to 69 and men 70 to 79 with T-scores at the spine, total hip, or femoral neck of −1.5 or less
• Postmenopausal women and men 50 and older with any of the following:
• Low-trauma fracture during adulthood
• Historical height loss of 1.5 inches (4 cm) or more
• Prospective height loss of 0.8 inches (2 cm) or more
• Recent or ongoing long-term glucocorticoid treatment [2]

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• Medical conditions associated with osteoporosis
• Hyperparathyroidism - may be primary or secondary; marked by elevated calcium and PTH levels
• Cushing's syndrome - excess endogenous cortisol; may be caused by pituitary (ACTH) or adrenal disorder (adrenal adenoma); see hypothalamic-pituitary-adrenal axis
• Gastrointestinal disorders (celiac disease, inflammatory bowel disease, gastric bypass, etc.) - decreased calcium and vitamin D absorption
• Hyperthyroidism
• End-stage kidney disease - reduced renal conversion of calcidiol to calcitriol and decreased phosphate excretion, leading 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
• 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

• Medications associated with osteoporosis
• Anticonvulsants - specifically carbamazepine, phenobarbital, phenytoin, and primidone; reduce vitamin D metabolism through CYP enzyme induction
• Aromatase inhibitors - block estrogen synthesis; used to treat and prevent breast cancer; drugs include Anastrozole (Arimidex®) and Exemestane (Aromasin®)
• Depo Provera® - suppresses estrogen levels
• Glucocorticoids - Chronic corticosteroid use; see glucocorticoid-induced osteoporosis for more
• Lithium - can raise parathyroid levels, promoting bone mineral loss
• SGLT2 inhibitors - particularly canagliflozin; have been shown to decrease BMD and increase fracture risk
• Proton pump inhibitors - in observational studies, long-term (> 1 year) PPI use has been associated with an increased risk of fracture; calcium absorption may be reduced by acid-reducing agents
• Glitazones (Actos, Avandia) - see glitazones and fractures
• Thyroid hormone replacement - excessive thyroid hormone replacement can cause osteoporosis
• Immunomodulators - methotrexate, cyclosporine, tacrolimus, etc.
• GnRH agonists - Leuprolide (Lupron®), Goserelin (Zoladex®), etc.; used to treat prostate cancer and endometriosis; induce hypogonadal state

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• 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 an increased fracture risk in some studies. However, other studies have found no increased risk with doses under 5 mg/day. [7]
• ACR recommendations for the treatment and prevention of glucocorticoid-induced osteoporosis are provided in the table 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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• Physiology
• Vitamin D
• Vitamin D's primary function is to regulate calcium levels, which it does through the following mechanisms: (1) stimulation of calcium and phosphorus absorption from the intestine; (2) enhancement of calcium reabsorption in the kidneys; and (3) mobilization of calcium stores from bone (see calcium regulation for more).
• Calcium
• Calcium and phosphate combine to form hydroxyapatite, the mineral that gives bones strength. In humans, 99% of calcium is found in bones, and 1% is in the extracellular space, where it is tightly regulated because it plays an important role in nerve conduction and muscle contraction (see calcium regulation). When dietary calcium is inadequate to maintain serum levels, calcium is resorbed from bone. Chronic resorption can reduce bone mineral density and increase fracture risk. [1]

• Supplements for OP prevention
• Randomized trials (see osteoporosis studies) evaluating the effects of vitamin D and calcium supplementation on fracture risk and BMD have not shown a conclusive benefit. The USPSTF recommends against supplementation with vitamin D with or without calcium for the primary prevention of fractures in community-dwelling postmenopausal women and men age 60 years or older. [3]

• Vitamin D
• Vitamin D serum levels
• Vitamin D recommended dietary allowance
• Vitamin D supplements

• Calcium

• 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)

• Daily doses > 500 mg should be divided to improve absorption
• Reference [2]

Calcium supplements
Calcium carbonate (40% elemental calcium) Common OTC calcium supplement. Inexpensive. Brand names include Caltrate and Os-Cal. 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% elemental calcium) Available in powder forms over the counter Primarily used to treat hyperphosphatemia in chronic kidney disease
Calcium citrate (21% elemental calcium) Common OTC calcium supplement. More expensive than calcium carbonate. OTC brand Citracal. Absorption is not affected by food or acid-reducing agents (e.g., H2 blockers, PPIs)
Calcium lactate (13% elemental calcium) Often used as a food additive
Calcium gluconate (9% elemental calcium) Typically given intravenously Powder form is used as a food additive

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• 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)