Osteoporosis: The Most Common Bone Metabolic Disorder

1. GENERAL PRINCIPLE

1.1 Definition

Osteoporosis is a common bone disorder characterized by a reduction in bone mineral density (BMD) and bone quality, leading to a decrease in bone strength or toughness. Bone density is a measure of the amount of minerals in a certain area or volume of bone, and is a function of peak bone mass and the rate of bone loss over time. Bone quality is determined by the macro- and micro-structure of bone, mineralization processes, bone turnover rate, and accumulation of microdamage. The process of osteoporosis results in a decrease in bone mass, destruction of bone structure, and an increase in bone fragility and the risk of fracture.

1.2 Epidemiology

Osteoporosis is the most common bone metabolic disorder. Low bone mass and osteoporosis affect more than 53 million people (8 million women and 2 million men with osteoporosis, and 43 million with low bone mass) in the United States and 200 million people worldwide. The progression from low bone mass to osteoporosis increases with age.

There are differences in the prevalence of the disease among ethnic/racial groups, as reported in older women from recent data in the 2005-2010 National Health and Nutrition Examination Survey (NHANES), with rates of low bone mass and osteoporosis of 52% and 15%, respectively, in non-Hispanic white women, 36% and 7% in non-Hispanic black women, and 47% and 20% in Mexican American women.

Osteoporotic fractures, especially hip fractures, are associated with significantly increased rates of disability and mortality in the short and long term, with estimated economic costs of up to 25 billion USD by 2025 due to the consequences of an aging population.

To reduce the burden of osteoporotic fractures, early detection and appropriate intervention for patients at high risk of fracture are necessary. Advances in diagnostic screening have made osteoporosis diagnosis easier. Many available treatments in various clinical settings can increase bone density and reduce fracture rates. Unfortunately, a significant proportion of patients with osteoporosis, including those who have had previous fractures, remain undiagnosed and untreated.

1.3 Bone Physiology and Pathology

The total mineral content of adult human bones depends on the peak bone mass achieved during early adulthood (25-30 years old) and the bone loss associated with aging and estrogen deficiency in women. Peak bone mass is mainly determined by genetic, racial/ethnic, and gender factors, along with contributions from environmental and metabolic conditions (nutritional status, calcium intake, physical activity, smoking, alcohol use, hormonal deficiencies, and other comorbidities). Men and black women have higher peak bone mass, which may explain their lower rates of osteoporosis and fractures.

Osteoporosis may result from failure to attain the expected peak bone mass in the first two to three decades of life, excessive bone remodeling (resorption exceeding formation), and age-related bone loss. Age-related bone loss occurs at a rate of 0.5-1% per year. Steroid sex hormone deficiency appears to be a major contributor to bone loss in older adults. Accelerated bone loss occurs during the menopausal transition in women due to the loss of estrogen’s inhibitory effects on bone resorption. Bone loss associated with menopause is most pronounced in trabecular bone (e.g., spine), where the bone loss rate can reach 3-5% per year over ten years. Focal bone loss (e.g., proximal femur, distal radius, and vertebrae) occurs more gradually. Because men have higher peak bone mass, larger bone cross-sectional areas, and no corresponding menopausal transition, their risk of bone loss and fracture does not increase significantly until they reach the age of 65-70 years. The loss of bone mass and increased fracture risk become more severe due to age-related functional decline, leading to increased fall and balance impairment risks, combined with an increased risk of fractures.

1.4 Risk factors

Several independent risk factors have been shown to be associated with low bone mass (Table 26.1). Some of these risk factors are modifiable, and it is important to address them in a comprehensive protocol for preventing or treating osteoporosis.

A range of chronic medical conditions and secondary causes of bone loss due to medications are listed in Table 26.2.

Fractures in osteoporosis are typically the result of falls. Therefore, risk factors for falls, independent of factors causing low bone mass, are important contributors to the disability associated with osteoporotic fractures (Table 26.3).

1.5 Co-existing conditions

Osteoporotic fractures:

Fractures of brittle bones are the primary cause of disability and death in adults with osteoporosis. The most common sites of osteoporotic fractures are the hip, spine, and wrist. Approximately 1.5 million osteoporotic fractures occur annually in the United States (700,000 vertebral, 300,000 hip, 200,000 wrist, and 300,000 other sites) [5]. A white woman at age 50 has a lifetime risk of osteoporotic fracture of 40% (compared with a risk of 23% in men). With the aging of the population, osteoporotic fractures are predicted to increase several-fold worldwide by the year 2050.

Table 26.1. Risk factors for osteoporosis and bone fractures

Female gender.

White race.

Advanced age.

Personal history of bone fractures.

Family history of osteoporosis/bone fractures in first-degree relatives.

Small body frame/low body weight.

Sedentary lifestyle/low physical activity.

Smoking.

Excessive alcohol consumption (more than 2 drinks per day).

Inadequate calcium and Vitamin D intake.

Excessive caffeine consumption.

Premature ovarian failure or early menopause (due to endocrine or surgical causes), (age under 45).

Frequent falls.

Fracture of the femoral neck is the most serious cause of disability and death, which can be attributed to osteoporosis. In the first year after a femoral neck fracture, the mortality rate is 20%, 50% lose their ability to perform daily activities independently, and only 30% regain their pre-fracture level of function. The cost of treating femoral neck fractures and their complications was estimated to be around 14 billion USD in 1995 and 17 billion USD in 2001.

Vertebral fractures often have no symptoms (only one-third of cases have clinical manifestations) and can be caused by everyday activities. Vertebral fractures, when combined with a state of disability, can lead to chronic back pain, decreased height, spinal deformity, restricted lung function, or gastrointestinal complications, which have been shown to decrease the quality of life of patients. Longitudinal studies have shown that vertebral fractures, whether symptomatic or not, are associated with an overall increased risk of mortality ranging from 15-30%. Fractures due to previous osteoporosis are the biggest risk factor for future fractures, with a relative risk ranging from 1.4-4.4 depending on the location of the initial fracture.

Table 26.2. Causes of secondary osteoporosis:

Endocrine disorders

Hyperthyroidism
Hypogonadism (primary or secondary)
Anorexia/ excessive dieting
Cushing’s syndrome/ hypercortisolism
Type 1 or 2 diabetes mellitus
Hyperparathyroidism
Hyperprolactinemia
Acromegaly
Hypogonadism (primary or secondary)
Adrenal insufficiency

Inherited disorders/ collagen disorders

Ehlers-Danlos syndrome
Glycogen storage diseases
Homocystinuria
Hypophosphatasia
Osteogenesis imperfecta porphyria

Gastrointestinal/ liver disorders

Celiac disease
Cholestatic liver disease
Malabsorption syndromes
Cirrhosis
Gastric bypass surgery/ gastric bypass
Sepsis
Inflammatory bowel disease

Hematological disorders

Amyloidosis
Leukemia/ lymphoma
Multiple myeloma
Monoclonal gammopathy of undetermined significance
Plasma cell dyscrasias

Infections

HIV/AIDS

Disorders of metabolism/nutrition:

Alcoholism
Elevated blood homocysteine
Low blood calcium
Malabsorption
Smoking
Vitamin D deficiency

Nervous system disorders:

Epilepsy
Muscular dystrophy
Spinal cord injury

Respiratory disorders:

Chronic obstructive pulmonary disease

Kidney disorders:

Chronic kidney disease (due to any cause)
Increased urinary calcium excretion
Nephrotoxicity from drugs

Low/immune system disorders:

Ankylosing spondylitis
Rheumatoid arthritis
Systemic lupus erythematosus
Systemic mastocytosis

Drug-induced:

Aluminum
Anticonvulsants (dilantin, phenobarbital)
Aromatase inhibitors
Cyclosporine
Glucocorticoids
Gonadotropin-releasing hormone agonists
(e.g., Lupron)
Long-term use of heparin
Methotrexate
Protease inhibitor drugs
Tamoxifen
Thiazolidinediones
Excessive thyroxine replacement therapy

2. Diagnosis of osteoporosis

2.1 Clinical manifestations

All postmenopausal women and men over the age of 50 should be evaluated for the risk of osteoporosis.

Most osteoporosis patients have no symptoms until they experience a fracture. Therefore, it is important to conduct a thorough evaluation of the patient’s medical history and physical signs to identify those at high risk for osteoporosis or fractures due to osteoporosis, as these are the individuals who will benefit from further diagnostic testing and treatment. Learn about the risk factors for low bone mass, fractures, and falls (Tables 26.1-26.3). During the physical examination, look for signs suggestive of a fracture such as a significant decrease in height compared to previous measurements (1.5 inches or 4 cm), previous fracture sequelae, and deformities or disabilities contributing to the risk of fractures (reduced height, kyphosis, rigid spinal column, chest deformity, rib-saddle angle, respiratory difficulty, abdominal bloating, posture, balance, and muscle strength) or suggestive of secondary osteoporosis (hyperthyroidism, Cushing’s syndrome).

Table 26.3. Risk factors that make patients prone to falls

History of falls.
Cognitive impairment.
Visual impairment.
Poor physical condition/weakness.
Issues with footwear or inappropriate shoes.
History of stroke or Parkinson’s disease.
Environmental risk factors.
Use of benzodiazepines, anticonvulsants, or anticholinergic medications.

Assessing the risk of bone fracture: Combining bone density and clinical risk factors provides a better prediction of fracture risk than using either criterion alone. The World Health Organization (WHO) has developed the Fracture Risk Assessment Tool (FRAX), an algorithm that estimates the 10-year probability of hip or major osteoporotic fracture (including spine, hip, proximal humerus, and distal forearm) by using easily collected information from clinical risk factors and bone mineral density (BMD) of the hip or the T-score, if available. The FRAX tool is available online at www.sheffield.ac.uk/FRAX or www.nof.org or in the software of newer generation DXA machines. This tool integrates age, sex, ethnicity, geographic location, weight, height, personal and family history of fracture, smoking, glucocorticoid use, diagnosis of low bone mass, alcohol use, presence of secondary osteoporosis (type 1 diabetes, osteogenesis imperfecta), untreated hypogonadism, early menopause (<40 years), chronic malnutrition or malabsorption or chronic liver disease) and BMD of the hip or T-score to estimate the risk of fracture. If the BMD result of the hip is known, the secondary osteoporosis section will no longer be used in the algorithm. The FRAX tool should be used for patients without a history of osteoporotic fracture and with a T-score greater than -2.5 but less than -1.0 (osteopenia) to provide a score estimate of fracture risk and potentially identify patients who may be candidates for treatment. However, this assessment tool may underestimate or overestimate the actual risk because it does not take into account the dose, duration, or severity of exposure (e.g., in glucocorticoid users), other contributing risk factors such as falls, the degree of bone fragility or spinal BMD. FRAX is also not validated for patients who are already receiving or have received treatment and cannot be used to monitor treatment response. Patients may be considered “untreated” if they have discontinued osteoporosis treatment for 1-2 years.

2.2 Diagnosis criteria

The World Health Organization (WHO) has established osteoporosis diagnostic criteria based on BMD and the T-score of the lumbar spine, hip or femoral neck. The T-score is used for women before or after menopause and men aged ≥ 50 [10,11].

Normal: BMD within 1 SD of the average reference value for young adults (T ≥ −1.0).
Low bone mass (“osteopenia”): BMD between 1 and 2.5 SD below the average reference value for young adults (2.5 < T < –1.0).
Osteoporosis: BMD > 2.5 SD below the average reference value for young adults (T ≤ −2.5).
Severe or established osteoporosis: BMD > 2.5 SD below the average reference value for young adults (T ≤ –2.5) and one or more fragility fractures due to osteoporosis.

Some professional associations have established criteria for the diagnosis of osteoporosis. The consensus is that when there are fragility fractures or fractures following mild trauma (such as falling from a standing height or less), T ≤ −2.5 or a combination of low bone mass (T-score between –1 and –2.5) plus high FRAX score appropriate for osteoporosis, osteoporosis should be diagnosed. All patients diagnosed with osteoporosis should be evaluated for secondary causes (Tables 26.2 and 26.4).

In premenopausal women and men under 50, the International Society for Clinical Densitometry (ISCD) recommends using the Z-score.

“In the expected age range: BMD within 2.0 SD of the average reference value (Z > –2.0).
“Below the expected age range”: BMD ≥ 2.0 SD below the average reference value (Z ≤ −2.0).”

Table 26.4. Diagnosis of osteoporosis.

The National Osteoporosis Foundation (NOF) of the United States

– Fracture of the hip or spine due to mild trauma in adults (≥50 years old).
– Lumbar spine, femoral neck or hip region: BMD ≥ 2.5 SD below the mean reference value of young adults (T-score ≤ -2.5).

The American Association of Clinical Endocrinologists and the National Osteoporosis Foundation

– Fracture of the hip or spine due to minor trauma. Lumbar spine, hip joint, femoral neck, or 33% radius: BMD = 2.5 SD below the mean reference value of young adults (T-score ≤ -2.5).
– Low bone mass (-1 < T < -2.5) plus fractures due to osteoporosis of the proximal humerus, pelvis, or distal forearm.
– Low bone mass (-1 < T < -2.5) plus high FRAX based on specific thresholds for the country regarding the risk of fracture adapted for the US, ≥ 3% probability of hip fracture within 10 years and ≥ 20% probability of any fracture within 10 years due to osteoporosis.

2.3 Diagnosis and clinical evaluation

2.3.1 Clinical evaluation

Clinical evaluations for men and women over menopausal age without symptoms of osteoporosis can identify the primary causes, which are 32% in men and 75% in women.

Basic investigations should include: biochemical testing (calcium, phospho, creatinine), liver function tests (including liver transaminases, alkaline phosphatase, total protein, serum albumin), 25-hydroxyvitamin D (25[OH]D), complete blood count, and testosterone levels in men.

Additional tests may be necessary depending on the clinical indication, such as intact parathyroid hormone (iPTH), 24-hour urine calcium and creatinine, thyroid function tests, serum or urine electrophoresis, 24-hour urine cortisol levels, and antibodies to assess gluten-free disease.

Bone turnover markers (BTMs) are enzymes involved in bone formation and resorption or by-products of collagen type 1 degradation. Bone formation markers include bone-specific alkaline phosphatase in serum, osteocalcin, and propeptides with N-terminal collagen type 1 (P1NP). Bone resorption markers include C-telopeptide (CTX) and N-telopeptide (NTX).

BTMs should not be used to diagnose osteoporosis. They provide dynamic information about bone turnover activity and may help understand the mechanism of bone loss. However, the high variability of BTM analysis and biological variability can limit their application in clinical practice. Recently, the International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine Working Group on Bone Markers have identified serum PINP and CTX as reference bone turnover markers, which may be useful in predicting fracture risk and monitoring osteoporosis treatment. The Bone Health Alliance has agreed on standardized steps for sample collection and processing, as well as patient preparation to reduce variability, including fasting morning CTX sample collection.

Table 26.5. Proposed guidelines for screening bone mineral density (BMD) for osteoporosis by the National Osteoporosis Foundation (NOF) and the International Society for Clinical Densitometry (ISCD).

The National Osteoporosis Foundation, International Society for Clinical Densitometry recommends:

Recommendations for women

– All women aged ≥65 years.
– Younger women around or after menopause who have suffered a fracture due to low trauma after age 50 or have clinical risk factors for fracture or low bone mass.
– Adults of any age with high risk factors or medication use associated with bone loss.

Recommendations for Men:

– All men ≥ 70 years old.
– Men 50 – 69 years old with fractures due to osteoporosis after age 50 or with risk factors for osteoporotic fractures or low bone mass.
– Any age group with high risk or taking medications associated with bone loss.

The Endocrine Society of the United States

Recommendations for Women:

All women ≥ 65 years old.
All postmenopausal women with a history of fractures, low bone mineral density on X-ray, or systemic glucocorticoid use for 3 months or more.
Premenopausal or postmenopausal women with risk factors for osteoporosis (weight < 127 lbs [57.6 kg] or BMI < 20, family history of osteoporotic fracture, early menopause < 40 years old, smoking, or excessive alcohol intake).
Secondary osteoporosis.

Recommendations for Men:

None.

2.3.2 Bone densitometry

Bone mineral density (BMD) measurement is the standard for diagnosis and evaluation of osteoporosis in adults. Several X-ray imaging techniques are available to measure BMD, including central and peripheral dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT) of the spine and peripheral sites, and quantitative ultrasound (QUS).

DXA is the current gold standard method for assessing bone density. It is used to diagnose and classify osteoporosis, evaluate fracture risk, and monitor changes in BMD over time. This method has low radiation exposure (about 1/10 of traditional X-rays), good accuracy, and reproducibility.

BMD should be measured at the lumbar spine and proximal femur. The non-dominant forearm may be used (33%) for patients with obesity, hyperthyroidism, or if hip or spine BMD cannot be measured or interpreted. BMD reflects the mineral content of bone divided by the area measured (g/cm). In the lumbar spine, measurements are taken at L1-L4 vertebrae, and data on BMD for the entire L1-L4 spine and individually for each vertebra are provided. The femoral neck BMD has almost equal cortical and trabecular bone components, which is a strong predictor of fracture risk and is used in the FRAX assessment tool, while the hip BMD is used to monitor changes in bone mineral density.

BMD results are reported as compared with reference ranges and are normalized to the standard deviation of the reference population. The T-score uses the average peak BMD of healthy young white women as the reference value, while the Z-score uses the corresponding average BMD of the reference group by age, gender, and race. T-score (and Z-score) assessment is a specialized technique, and results obtained from different bone density assessment methods cannot be compared. DXA measurements should be performed on properly maintained and calibrated machines by trained technicians…

CT quantitative (QCT) and peripheral quantitative (pQCT) CT scanning measure bone mineral density (BMD) in units of volume (unit of measure is g/cm3) at central locations (hip joint and spine) and peripheral locations (radius and tibia). Additionally, QCT can separate bone mineral content by bone compartments, including trabecular bone, cortical bone, and subperiosteal bone spaces. High-resolution pQCT provides detailed in vivo microstructural images of bone, such as the density of cortical and trabecular bone structures. QCT of the hip in postmenopausal women can predict the risk of hip and spine fractures and monitor treatment and treatment-related changes. However, QCT is more expensive, involves higher radiation doses, and high-resolution peripheral quantitative CT (HRpQCT) is not always available for clinical use. Thus, DXA remains the preferred screening method.

Trabecular bone score (TBS) is a score, not a BMD, derived from DXA images of the lumbar spine obtained from some bone density measuring devices. This score is associated with vertebral fractures, hip fractures, and major osteoporotic fractures in postmenopausal women, as well as major fractures in men over 50 years old with osteoporosis. The fracture risk is partly independent of BMD measured by DXA and clinical risk factors. TBS has been approved by the FDA and the European Health Organization as an additional index for DXA and FRAX, but it should not be used alone to guide treatment decisions.

Peripheral bone density measurement (excluding the hip) can be performed using DXA, QCT, or quantitative ultrasound (QUS). The measured sites include the forearm, fingers, and heel. The benefits of peripheral bone density measurement techniques are that the machines can be easily moved, and the technique can be performed at an initial health examination using QUS. Although these screening methods have been shown to predict fracture risk, there is no universally accepted diagnostic standard for many devices currently available on the market. Peripheral bone density screening is not recommended for diagnosing osteoporosis. If abnormal results are found, the measurement should be repeated by a DXA central facility to confirm the results and make a diagnosis.

Conventional X-ray is an unreliable method for assessing bone mass because it can take up to 30 minutes to detect changes in bone density, which are not always sensitive enough to detect osteoporosis.

Spinal imaging surveys using either conventional X-ray films or vertebral fracture assessment (VFA) from DXA will provide accurate evaluations for vertebral fractures that may be asymptomatic. Spinal imaging should be considered in the following subjects: Women ≥70 years and men ≥80 years if the BMD T-score is ≤–1.0 at the lumbar spine, hip joint, and femoral neck; women aged 65-69 and men aged 70-79 if the BMD T-score is ≤–1.5 at the lumbar spine, hip joint, and femoral neck; Postmenopausal women and men ≥50 years with a history of low-trauma fracture after the age of 50, a height loss of 1.5 inches (4 cm) from previous height, an expected height loss of 0.8 inches (2 cm), or recent long-term glucocorticoid use.

3. Treatment of osteoporosis

The goal of intervention is to prevent fractures. Treatment decisions should be individualized based on consideration of the patient’s comorbidities, clinical risk factors, and patient preference. Treatment decisions in a specific case should be made in collaboration with the patient.

Lifestyle and non-pharmacological interventions (see Lifestyle/FRAX) as well as pharmacological therapy should be recommended for all adult individuals, including those who do not meet the criteria for specific anti-osteoporosis therapy.

3.1 Pharmacological Treatment

Indications for pharmacological therapy (6,12): FDA-approved therapies should be considered in postmenopausal women or men over the age of 50 with:

Hip or vertebral fracture after minimal trauma.

DXA T-score ≤ −2.5 (osteoporosis) at the lumbar spine, total hip, or femoral neck.

DXA T-score between -1.0 and -2.5 (low bone mass) with a 10-year FRAX probability of hip fracture >3% or a major osteoporotic fracture >20% in the US or based on specific thresholds for each country.

3.1.1 First-line Drug Choices

For information about FDA-approved osteoporosis pharmacotherapy, see Tables 26.6 and 27.7.

Aminobisphosphonates, including alendronate, risedronate, ibandronate, and zoledronic acid, are the most widely used drugs to treat osteoporosis. These drugs are currently available on the market in generic form. The chemical structure of bisphosphonates resembles pyrophosphate, which binds to hydroxyapatite crystals at sites of active bone restructuring, thereby strongly inhibiting bone resorption through osteoclastic activity. This helps improve bone density after three years, reducing the risk of hip and vertebral fractures (except for ibandronate, which has only been shown to reduce vertebral fractures).

Bisphosphonates for oral administration include alendronate, risedronate, and ibandronate. Alendronate is available on the market with supplemental vitamin D, and risedronate is available with supplemental calcium. Oral bisphosphonates are poorly absorbed, so they should be taken early in the morning with a glass of water after an overnight fast, and the patient should not lie down, eat, or drink any other medication for at least 30 minutes. Atelvia, a slow-release formulation, should be taken after breakfast but still requires the patient to remain upright for 30 minutes after taking the medication. In randomized, controlled trials with placebo, no significant differences in gastrointestinal side effects were observed between treatment and placebo. Treatment protocols using a monthly or more recent weekly dosage have improved patient compliance with treatment. However, in clinical practice, about 10% of patients experience gastrointestinal side effects, and severe erosive esophagitis related to the medication’s “backflow” has been reported. This is a rare but serious complication.

Bisphosphonates for intravenous use, including ibandronate and zoledronic acid, are preferred for patients who have poor absorption, do not tolerate oral medication, or are unable to remember to use bisphosphonates orally. “Flu-like” reactions during infusion have been observed and can be reduced by pretreatment with paracetamol. Renal failure has been reported when using intravenous bisphosphonates, so blood creatinine levels should be checked before each infusion. Atrial fibrillation has been reported in one trial using zoledronic acid but has not been confirmed in other trials with the same drug or with a different bisphosphonate.

Contraindications for using oral or intravenous bisphosphonates include hypersensitivity, low blood calcium, and renal failure (glomerular filtration rate [GFR] <30 mL/minute for risedronate and ibandronate or <35 mL/minute for zoledronic acid).

Osteonecrosis of the jaw (ONJ) is a rare complication associated with the use of bone resorption inhibitors, occurring in 1/10,000 – 1/100,000 patients. This condition is characterized by non-healing wounds, exposed bone in the maxillofacial region, detected by healthcare professionals within 8 weeks of treatment with bone resorption inhibitors (bisphosphonates or denosumab), and with no history of radiation to the maxillofacial area. Risk factors include high cumulative doses of bone resorption inhibitors, which are commonly administered by injection for cancer treatment (much less frequently for osteoporosis), invasive oral surgery, infection, and poor oral hygiene. In high-risk patients, treatment with bone resorption inhibitors should be delayed or stopped until after oral surgery, until mucosal healing is complete, or oral surgery should be avoided if possible during treatment with these medications. As the risk is much lower in patients with osteoporosis, the American Dental Association recommends that bisphosphonates do not need to be discontinued before dental procedures. Treatment involves local mouthwash with antibiotics, systemic antibiotics, and surgical removal of necrotic bone in some rare cases.

Atypical femoral fractures (AFF) have been reported in patients receiving bone resorption inhibitors (bisphosphonates and denosumab) and also occur in those not receiving these medications. These are non-traumatic fractures located along the shaft of the femur (between the lesser trochanter and the supracondylar flare), characterized by lateral or transverse orientation, a minimal or no displacement, and thickening of the lateral or medial femoral cortex at the fracture site. Other notable features are thickening of the femoral shaft, prodromal symptoms (pain in the groin or thigh), bilateral involvement, and delayed healing of the fracture. The pathogenesis is not well understood and may be related to altered bone quality and prolonged suppression of bone remodeling. Although the risk is relatively high with bisphosphonate use (OR 2.1-66), the absolute risk is still very low. Some epidemiological studies suggest that the risk increases with longer use, with adjusted incidence rates increasing from 1.8/100,000 per year for 2 years of use to 113/100,000 per year after 8 years of use.

Selective estrogen receptor modulators (SERMs) demonstrate selective antagonistic or agonistic effects on various targets, providing the advantage of retaining beneficial effects and minimizing the adverse effects of estrogen. Raloxifene (Evista) has estrogenic effects, anti-estrogenic effects, and neutral effects on bone, breast, and uterine tissue. The drug is FDA-approved for osteoporosis prevention and reducing breast cancer risk. Treatment for 3 years has been shown to improve BMD (spine and hip) and reduce the incidence of new vertebral fractures but not reduce hip or other non-spinal fractures. Treatment for 5 years in postmenopausal women with coronary artery disease or risk factors for coronary artery disease does not increase the risk of first-time coronary artery events but increases the risk of venous thromboembolic events and fatal stroke (both are included in the black box warning), although the overall mortality rate is similar to placebo. Reported side effects are hot flashes, leg cramps, and peripheral edema. Raloxifene may be considered for postmenopausal women with low BMD advantage at the spine and preserved BMD at the hip and high risk of breast cancer when these patients cannot tolerate bisphosphonates. Raloxifene should be discontinued at least 72 hours before surgery in patients at risk for venous thromboembolism.

Bazedoxifene/estrogen combination (Duavee) is a tissue-selective estrogen complex (TSEC), a combination of a SERM with estrogen. The drug has estrogenic activity on bone, antiestrogenic activity on the breast and uterus and is FDA-approved for preventing postmenopausal osteoporosis and treating menopausal vasomotor symptoms. Phase 3 trials show increased BMD at the lumbar spine and hip, decreased bone turnover marker (BTM) levels, and improved vasomotor symptoms. The endometrial hyperplasia rate is low compared with hormone replacement therapy (HRT), and breast density and breast pain are less frequent. Reported side effects include muscle spasms, diarrhea, nausea, and dizziness. Due to containing estrogen, Duavee use requires adherence to all precautions and black box warnings similar to estrogen. However, there is currently no data on fracture risk associated with Duavee use. Bazedoxifene (Conbriza) is approved in Europe for the treatment of…

Teriparatide (Forteo) is a 34-amino acid recombinant PTH peptide with an N-terminal group that stimulates bone formation. Interestingly, prolonged exposure to primary hyperparathyroidism increases bone resorption, while intermittent exposure to PTH stimulates bone formation. The medication is administered as a daily subcutaneous injection at a dose of 20 mcg.

Treatment for 18 months in postmenopausal women at risk of vertebral fracture increases BMD (spine and hip), reduces vertebral and non-vertebral fractures. However, studies are not strong enough to investigate the ability to reduce hip fractures. Teriparatide use is usually reserved for patients with severe osteoporosis who cannot tolerate or do not respond to bisphosphonates.

Reported adverse effects include nausea, headache, dizziness, leg cramps, and transient increases in blood calcium levels. Very high doses in mice cause an increased incidence of bone sarcoma, although this has not been observed in human trials. Therefore, teriparatide has a black box warning regarding the risk of sarcoma and is contraindicated in patients with pre-existing hypercalcemia, bone metastases, or in those at risk of bone sarcoma (Paget’s disease, previous radiation to bone, open bone wounds, or unexplained elevation of alkaline phosphatase). Treatment with the drug should not be recommended for more than 2 years.

BMD at the hip and spine decreases after stopping teriparatide for 6 months, but the reduced risk of vertebral and non-vertebral fractures persists for 18 months (for vertebral fractures) and 30 months (for non-vertebral fractures). Using bisphosphonates after teriparatide treatment helps to maintain or further increase BMD obtained from teriparatide treatment. Therefore, anti-resorptive drugs, usually bisphosphonates, are started after teriparatide to maintain BMD.

Denosumab (Prolia) is a monoclonal antibody against the receptor activator of nuclear factor kappa B ligand (RANKL), which is a cytokine produced by osteoblasts that stimulates the differentiation, activity, and survival of osteoclasts, thereby inhibiting bone resorption. Similar to bisphosphonates, denosumab also inhibits bone formation through the inhibition of osteoclast-mediated bone resorption. Denosumab is approved for the treatment of postmenopausal women with osteoporosis, men with osteoporosis at high risk of fracture, and patients at high risk of bone loss undergoing androgen-deprivation therapy for prostate cancer or aromatase inhibitor therapy for breast cancer. It is administered by subcutaneous injection at a dose of 60 mg every 6 months.

In postmenopausal women with osteoporosis (23% of whom had a previous vertebral fracture and a mean T-score at the spine of –2.8), 3 years of denosumab treatment improved bone mineral density (at the spine and hip), inhibited bone turnover markers (BTMs), reduced the risk of vertebral, hip, and nonvertebral fractures. The reduction in fracture risk was similar to that observed with zoledronic acid and teriparatide. A 10-year extension study demonstrated continued reductions in fracture risk, sustained BTM suppression, and maintenance of BMD at the hip and spine.

As with other antiresorptive agents, hypocalcemia and hypersensitivity are contraindications to the drug. Reported adverse effects include skin infections, eczema, and pancreatitis. No dose adjustment is required for renal impairment. However, the frequency of hypocalcemia requires higher calcium and vitamin D supplementation. Ten-year treatment is well-tolerated and adverse event rates remain stable over time. However, two cases of atypical femur fracture (AFF) (in years 3 and 7) and 13 cases of osteonecrosis of the jaw (ONJ) have been reported (11 cases of which resolved while two discontinued the study and outcomes were not reported). The incidence of AFF and ONJ is thought to be dose- and duration-dependent. The optimal duration of denosumab therapy is not yet known. Some cases of spontaneous vertebral fractures occurring 9 to 16 months after discontinuing denosumab and without using other treatments have been reported. BTMs increase to above baseline values when denosumab is stopped after 2 years of use.

3.1.2 Second-line treatment options

Estrogen/ Hormone replacement therapy (HRT) can improve bone mineral density by inhibiting osteoclast activity. According to the Women’s Health Initiative (WHI), a combination of estrogen and progesterone improved BMD (spine and hip) and reduced fracture risk (total, vertebral, hip, and lower arm) [54,55]. However, the WHI also found that HRT increased the risk of coronary artery disease by 29%, stroke by 41%, venous thromboembolism by 111%, and invasive breast cancer by 26%. Thus, the risks may outweigh the benefits of reducing fracture risk. Currently, there are other medications available on the market that have better treatment efficacy and safety profiles, which is why HRT is no longer popular for preventing and treating osteoporosis. In women considering HRT for relief of menopausal symptoms, the lowest effective dose should be used for the shortest duration possible to achieve benefits in BMD and fracture risk reduction. However, other treatment options should be considered first for preventing osteoporosis in women who have no other indication for HRT.

Calcitonin (Miacalcin) is an endogenous peptide that inhibits osteoclast activity. The nasal spray formulation of calcitonin approved by the FDA is indicated for the treatment of postmenopausal osteoporosis for women who are either contraindicated or intolerant to first-line agents and have been postmenopausal for at least 5 years. The improvement in spine BMD is much less than that seen with other medications and is minimal in the hip. The 200 IU/day dose reduces vertebral fracture risk after 5 years but has no significant effect on hip or nonvertebral fractures. The intranasal formulation may cause nasal irritation and epistaxis. Calcitonin nasal spray has analgesic effects and may help to reduce pain associated with acute vertebral compression fractures.

3.1.3 Unapproved drugs by FDA

Strontiranelate, a strontium salt of ranelic acid, is approved in some European countries for the treatment of osteoporosis. Studies have shown that the drug reduces 40% of vertebral fractures and 36% of hip fractures in a subgroup of elderly patients. The mechanism of action of the drug is still not fully understood, but the combination of the drug during the mineralization phase of bone may explain the observed increase in bone density. In general, the drug is well-tolerated. However, in 2013, the European Medicines Agency (EMA) issued a warning about an increased risk of heart muscle infarction associated with strontium ranelate based on their evaluation of data from initial clinical trials. Strontium ranelate is not approved by the FDA in the United States, but strontium citrate is available over-the-counter in the US, and this formulation has no clinical data on fractures.

Hydrochlorothiazide (HCTZ) is a thiazide diuretic used to treat hypertension. The drug is not approved for the treatment of osteoporosis. In a large cohort treated for > 1 year with hydrochlorothiazide, it was found to increase BMD and reduce hip fractures. By inhibiting the sodium-chloride co-transporter (NCC) in the renal tubules and promoting calcium reabsorption, hydrochlorothiazide is an effective treatment for hypercalciuria, a condition that may contribute to bone loss. Thiazides have been shown to stimulate osteoblast differentiation in human osteoblasts expressing the thiazide-sensitive sodium-chloride co-transporter, suggesting a direct bone-forming effect [61]. Electrolyte disorders, including hypercalcemia, are the most important adverse effects of hydrochlorothiazide and should be monitored in the elderly.

3.1.4 Combination Therapy

Various combinations of anti-osteoporotic medications have been studied. Adding alendronate or risedronate to hormone replacement therapy (HRT) has been shown to have an additional effect on bone density similar to the combination of raloxifene and alendronate. The combination of parathyroid hormone (PTH) and alendronate is less effective than teriparatide alone in improving BMD and increasing new bone formation. However, sequential treatment shows that BMD improvements after 1 year of PTH (1-84) treatment will be maintained or improved when continued with alendronate but will be lost if not followed by bisphosphonate treatment.

Combining denosumab and teriparatide for 2 years in postmenopausal women increases spine and hip BMD more than using a single drug alone. Furthermore, combination therapy for 2 years and then switching to denosumab for 2 years, as well as switching from 2 years of teriparatide to 2 years of denosumab, leads to a gradual increase in BMD of the spine, hip, and wrist bones. On the other hand, treating with denosumab for 2 years and then following up with teriparatide for another 2 years shows a progression or temporary status of bone loss. When teriparatide and denosumab treatment is stopped after 4 years, there is a rapid improvement in lost bone density. However, this bone loss condition can be prevented in patients receiving timely bone resorption inhibitor treatment, highlighting the importance of switching medications at the right time. Therefore, the current typical approach is to start bisphosphonate immediately after stopping teriparatide or denosumab treatment to maintain the achieved bone density, in the case of using denosumab, to prevent rebound vertebral fractures after stopping the medication. Combination therapy is not recommended for routine use.

3.1.5 Treatment duration

The treatment duration should be individualized. The FLEX study showed a lower risk of vertebral fractures but no change in non-vertebral or morphometric vertebral fractures after 10 years of alendronate use (compared to 5 years) [68]. Subgroup analysis showed that this treatment reduced non-vertebral fractures in patients with a hip bone T-score ≤ -2.5 and no vertebral fractures at baseline in the FLEX study. However, older patients with a BMD of the hip and femoral neck in the lowest third (T-scores ranging from -2.5 to -4.1 and -2.3 to -4.2, respectively) were at increased risk of fractures after discontinuing alendronate use at 5 years. In the HORIZON-PFT study, 6 years of zoledronic acid treatment (compared to 3 years) was associated with a significant reduction in new morphometric vertebral fractures but not non-vertebral or hip fractures. Further analysis showed that in participants who discontinued zoledronic acid after 3 years, those with a hip bone T-score ≤ -2.5 had a higher frequency of new morphometric vertebral fractures, while those with low femoral neck T-scores had a higher frequency of new non-vertebral fractures and vertebral fractures outside the spine. In patients with low risk (hip T-score > -2.5, no new fracture events observed), discontinuation of zoledronic acid after 3 years did not increase the risk of fractures in the subsequent 3 years. These data suggest a residual effect due to long-term bone retention, with continued benefits after 5 years of alendronate use and 3 years of zoledronic acid use in low-risk groups.

Due to concerns about long-term safety when using bisphosphonates, the American Society for Bone and Mineral Research (ASBMR) expert group recommends continuous use of bisphosphonates (oral) for 5 years, bisphosphonates (intravenous) for 3 years, and risk assessment. For patients who still have a high risk of fracture (older age, low hip T-score, high fracture score, previous severe osteoporotic fracture or fracture during treatment), consideration should be given to continuing treatment for an additional 5 years (oral) or 3 years (intravenous) with regular patient evaluations. For low-risk individuals, discontinuation of bisphosphonates may be considered after 2 to 3 years of treatment with regular patient evaluations.

As previously mentioned, rapid bone loss and spontaneous vertebral fractures have been observed after discontinuation of denosumab. Therefore, caution should be taken not to interrupt denosumab treatment and bisphosphonate or bone-forming agents should be started immediately after discontinuation. PTH-based treatments have recommended a cumulative treatment time of 24 months.

Once again, treatment decisions should be individualized, based on clinical judgment balancing risk and benefit and discussed with the patient.

3.2 Lifestyle changes/Risk factors

Lifestyle changes are essential for the treatment and prevention of osteoporosis. Adults with osteoporosis are encouraged to quit smoking and avoid excessive alcohol consumption.

3.2.1 Diet

Providing a diet rich in calcium and vitamin D is necessary to achieve peak bone mass and maintain bone mass throughout life after menopause. Fractures of the hip and non-spine fractures can be reduced by using calcium in combination with vitamin D compared to using 700-800 IU vitamin D alone, as reported in older adults. Calcium and vitamin D supplementation have been advocated in most osteoporosis trials.

Calcium:

The recommended elemental calcium intake is 1000 mg/day in women <50 years and men <70 years, 1200 mg/day in women over 50 years and men over 70 years. Calcium-rich foods include milk, yogurt, cheese, sardines, and fortified fruit juice. On average, 240 mL of milk, 180 mL of yogurt or 45 g of cheese contain 300 mg of elemental calcium. The average daily calcium intake from non-dairy food sources for adults is 250-300 mg/day, therefore, most individuals need guidance to optimize absorption.

There are various formulations of calcium supplements available over the counter, and patients should read the instructions to know the amount of elemental calcium in each tablet. Calcium carbonate contains 40% elemental calcium, while calcium citrate contains 21% elemental calcium. Calcium salts are best absorbed when taken with a meal, but citrate calcium can be taken outside of meals, and is less constipating.

A meta-analysis suggested that calcium supplementation in older adults was associated with an increased risk of cardiovascular disease. Since then, other studies have reported conflicting results with some studies suggesting an increased risk of cardiovascular disease while others show no or reduced risk. With regard to cardiovascular safety, the amount of calcium in the diet and total calcium intake should not exceed 1500 mg/day.

Vitamin D:

A serum 25(OH)D concentration of 30 to 50 ng/mL is suggested [6, 12]. Within this range, the mineral set point must be balanced with optimal calcium and mineral absorption in the gut. The recommended daily intake for adults ≥50 years old is 800 to 1000 IU/day. However, vitamin D deficiency is prevalent and serum 25(OH)D levels should be measured in all patients when they are evaluated for bone health. If deficiency is present, supplementation should be given according to guidelines.

Encouraging physical activity is crucial for patients to engage in regular weight-bearing exercises throughout their lives, as it has been proven to maximize peak bone mass in young women, reduce age-related bone loss, improve BMD in some cases, and maintain muscle balance and strength. Improving agility, posture, and balance can reduce the risk of falls. Nursing Health research has shown that postmenopausal women who perform three equivalent physical activities per week will reduce their hip fracture risk by 6%. Causes of falls can be reversed (such as overuse of medication, neurological or visual problems, poor footwear, and poor indoor environment) and should be evaluated and addressed.

4. Special Cases

Glucocorticoid-induced osteoporosis is the most common cause of secondary osteoporosis. Bone loss occurs early and rapidly (about 6-12% per year) in the first year, and the risk of fractures increases by 75% within the first three months of glucocorticoid use. The rate of bone loss is a function of the dose and duration of glucocorticoid use. Fractures due to osteoporosis occur even at low-risk bone density levels. Glucocorticoids inhibit the function of osteoblasts, cause programmed cell death of bone-forming cells, and prolong the lifespan of bone-resorbing cells, thereby shifting the balance toward bone loss and increasing the risk of fracture. In 2017, the American College of Rheumatology (ACR) issued guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis. Fracture risk assessment (comorbidities, fractures, falls, glucocorticoid dose) and BMD testing are recommended for patients starting glucocorticoid therapy with a prednisone-equivalent dose >2.5 mg/day for >3 months. The FRAX score must be adjusted for patients taking prednisone doses >7.5 mg/day by multiplying the 10-year fracture risk by 1.15 (for major osteoporotic fractures) and 1.2 (for hip fractures). Patients taking glucocorticoids with doses above this level are at moderate to high risk of fracture (previous fractures, hip or spine T-scores ≤ -2.5 or Z-scores < -3, estimated major osteoporotic fracture risk according to FRAX >10%, and more).

Diabetes is increasingly recognized as a risk factor for osteoporotic fractures. BMD is often decreased in type 1 diabetes patients, normal or even mildly increased in type 2 diabetes patients. However, both groups have an increased risk of fractures compared to non-diabetic individuals. Measuring BMD and estimating fracture risk using the FRAX tool underestimates the actual risk in type 2 diabetes patients, which clinicians need to be aware of [81]. The mechanisms leading to increased fracture susceptibility are multifactorial and include oxidative stress, chronic inflammation, hyperglycemia, accumulation of advanced glycation end products, alterations in collagen properties, and increased marrow adiposity. Some diabetes medications, such as thiazolidinediones, SGLT-2 inhibitors, and insulin, are associated with a higher frequency of fractures. Currently, the management of fracture susceptibility in diabetes patients is pursued similarly to the management of postmenopausal osteoporosis.

5. Monitoring

Patients undergoing treatment with medication need to be monitored for complications, side effects, adequate calcium and vitamin D intake, ongoing and emerging risk factors, as well as adherence and response to treatment. Regular assessment of modifiable risk factors and addressing them should be performed (see Tables 26.1, 26.2, and 26.3). Annual height measurements are recommended to screen for asymptomatic vertebral fractures.

Treatment response can be monitored by using bone mineral density (BMD) measurements by DXA or bone turnover markers (BTMs). To monitor changes in BMD at the spine and hip, DXA should be repeated every 2 years at the same medical facility, using the same calibrated machine and, if possible, by the same technician performing the scan. Finally, DXA monitoring may be performed depending on the clinical status of each patient, and comparison of BMD results should be done by using the same measuring device. Due to inherent variability in DXA-derived BMD results, precision analysis and least significant change (LSC) should be calculated for each medical facility according to ISCD recommendations. Facility-specific LSCs are typically set at 95% confidence interval, establishing the minimum significant change in BMD that exceeds measurement error. Follow-up intervals and testing protocols should be individualized based on clinical judgment, risk factors, and BMD status.