Continuing Education Activity

Osteopenia, or low bone mass, refers to reduced bone mineral density below normal values without fulfilling the diagnostic threshold for osteoporosis. Bone mineral density is determined by dual-energy x-ray absorptiometry (DXA). According to the World Health Organization, osteopenia corresponds to a T-score between -1.0 and -2.5, while a T-score less than -2.5 indicates osteoporosis. Osteopenia arises from an imbalance between bone resorption and formation, influenced by aging, estrogen deficiency, inadequate calcium and vitamin D intake, cigarette smoking, a sedentary lifestyle, and certain medications such as glucocorticoids. Most patients remain asymptomatic until a fracture occurs, often after minimal trauma.

Evaluation includes identifying secondary causes and estimating fracture risk with the aid of the Fracture Risk Assessment Tool (FRAX). Pharmacologic therapy is recommended for individuals with osteopenia who demonstrate a high 10-year probability of hip or major osteoporotic fracture, whereas those with low-to-moderate risk require nonpharmacologic management, including weight-bearing exercise, smoking cessation, and adequate calcium and vitamin D supplementation. Early diagnosis and risk reduction prevent progression to osteoporosis and fragility fractures.

This activity for healthcare professionals is designed to improve learners' competence in evaluating and managing osteopenia. Participants will advance their mastery of the condition's etiology, risk factors, pathophysiology, clinical presentation, and evidence-based diagnostic and therapeutic approaches. Enhanced proficiency will empower clinicians to collaborate with interprofessional teams caring for affected individuals.

Objectives:

• Identify the clinical and diagnostic features suggestive of osteopenia.
• Differentiate osteoporosis from osteopenia based on the T-score.
• Implement evidence-based, personalized strategies for managing osteopenia and mitigating its potential risks.
• Implement interprofessional team strategies to improve care coordination and communication, thereby enhancing outcomes for patients affected by osteopenia.

Introduction

Osteopenia, or low bone mass, refers to a reduction in bone mineral density (BMD) below normal reference values without fulfilling the diagnostic criteria for osteoporosis.[1] BMD is measured using dual-energy x-ray absorptiometry (DXA). According to the World Health Organization (WHO), osteopenia is defined by a T-score between -1.0 and -2.5, while a T-score less than -2.5 indicates osteoporosis. Decreasing BMD values reflect a disruption in bone microarchitecture, leading to diminished bone strength. Both osteopenia and osteoporosis represent quantitative rather than qualitative disorders of bone mineralization.[2]

Etiology

Bone mineral acquisition from birth to adulthood follows a predictable pattern determined by age and sex. Bone mineral accretion increases rapidly during puberty, reaching its maximum shortly after peak height velocity in adolescence. Accretion rates remain elevated for approximately 4 years after this peak, with about 90% of adult bone mass typically attained by ages 18 to 21 in female individuals and 20 to 23 in male individuals.[3][4] Peak bone mass is generally achieved by the 3rd decade of life.[5] Inadequate attainment of peak bone mass during young adulthood predisposes to early-onset reductions in bone density, manifesting as osteopenia or osteoporosis, and increases susceptibility to fragility fractures even in adolescence and early adulthood.[6][7] After age 30, bone mass declines gradually and progressively with advancing age.[8]

Heritable factors account for an estimated 60% to 80% of the capacity to achieve and maintain optimal bone mineralization.[9][10] Modifiable influences on the rate of bone loss in adulthood include engagement in weight-bearing exercise, adequate nutritional intake of calcium and vitamin D, maintenance of a healthy body mass, and hormonal balance.

The gradual loss of bone mass that occurs during adulthood represents the primary mechanism underlying osteopenia and osteoporosis. Acceleration of this process is driven by secondary causes that are lifestyle-based, such as alcohol use disorder, tobacco consumption, low physical activity levels, and body mass index (BMI) under 18.5 kg/m². Individuals of White or Asian ancestry exhibit an increased susceptibility to bone loss.[11][12][13]

Pathologic conditions and pharmacologic agents also contribute as secondary causes. Relevant medical disorders include hyperparathyroidism, anorexia nervosa, malabsorption syndromes, hyperthyroidism, chronic renal insufficiency, chronic liver disease, rheumatoid arthritis, hypogonadism, amenorrhea or oligomenorrhea, premature menopause, and chronic illnesses leading to calcium or vitamin D deficiency.[14][15][16] Medications associated with reduced bone density include long-term glucocorticoid therapy, valproic acid, proton pump inhibitors, antiepileptic drugs, excessive thyroid hormone replacement, and certain chemotherapeutic agents.[17]

Epidemiology

An estimated 43.3 million American adults older than 50 years have been diagnosed with osteopenia, accounting for approximately 44% of the population in this age group. Low bone mass affects nearly 50% of women and 30% of men older than 50 years.[18] The incidence is expected to increase markedly as the population continues to age. Adults older than 65 are projected to comprise more than 20% of the U.S. population by 2030, up from 13% in 2010.[19] Globally, osteopenia affects about 40% of adults, with prevalence varying among populations.[20] Approximately 1 in 3 women and 1 in 5 men older than 50 experience a fragility fracture, and nearly 1/3 of these fractures occur in older men.[21]

Fragility fractures substantially diminish quality of life and impose a growing economic burden on healthcare systems worldwide. In the U.S., approximately 2 million fragility fractures occur annually, with projections exceeding 3 million by 2040.[22][23] Worldwide, about 178 million fragility fractures occur each year.[24] Direct healthcare costs related to fragility fractures are estimated at $57 billion annually, with total direct and indirect expenditures expected to exceed $95 billion by 2040.[25] Osteopenia accounts for a substantial proportion of these costs because of its higher prevalence. Hip fractures, in particular, are associated with a 1-year mortality rate exceeding 20%, underscoring the condition’s significant public health impact.[26][27][28]

Diagnosis of osteopenia is critical because most fragility fractures occur in individuals within this range rather than among those with established osteoporosis.[29] Approximately 48% to 56% of fragility fractures in postmenopausal women and 42% of those in men older than 50 occur in individuals with osteopenia-level BMD.[30][31][32]

Causes of secondary osteoporosis include the following:

• Endocrine disorders: Hypogonadism (primary or secondary) in male and female individuals, hyperparathyroidism, hyperthyroidism, Cushing syndrome, diabetes mellitus, premature menopause, hyperprolactinemia, acromegaly, and vitamin D deficiency.
• Gastrointestinal, hepatic, and nutritional disorders: Celiac disease, malabsorptive syndromes, bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy), total gastrectomy, chronic liver disease, pancreatic insufficiency, malnutrition, and anorexia nervosa.
• Autoimmune disorders: Rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, inflammatory bowel disease, multiple sclerosis, and sarcoidosis.
• Connective tissue disorders: Osteogenesis imperfecta, Ehlers-Danlos syndrome, and Marfan syndrome.
• Hematologic disorders: Multiple myeloma, monoclonal gammopathy of undetermined significance, macroglobulinemia, leukemia and lymphoma, sickle cell disease, thalassemia, amyloidosis, mastocytosis.
• Renal disorders: Chronic kidney disease and idiopathic hypercalciuria.
• Drug-induced bone loss: Glucocorticoids, aromatase inhibitors, anticonvulsants, proton pump inhibitors, aluminum-containing antacids, gonadotropin-releasing hormone agonists and antagonists, chemotherapy, immunosuppressants, and heparin.
• Lifestyle factors: Alcoholism, smoking, and immobility.
• Other conditions: Hypophosphatasia, homocystinuria, spinal cord injuries, Parkinson disease, organ transplant, chronic obstructive pulmonary disease, HIV/AIDS, and Gaucher disease.[33][34][35][36]

Recognition of secondary causes is essential, as these conditions accelerate bone resorption or impair bone formation through distinct pathophysiologic mechanisms. Early identification allows clinicians to address reversible contributors and optimize treatment outcomes.

Pathophysiology

Bone density in adults reflects the balance between peak bone acquisition and subsequent age-related bone loss. Bone remodeling is a lifelong process involving continuous resorption and formation. These processes are closely coupled under normal physiologic conditions, maintaining skeletal integrity. Uncoupling of remodeling, in which bone resorption exceeds formation, results in progressive bone loss.

Osteoblasts are bone-forming cells responsible for matrix synthesis and mineralization. Osteoclasts are multinucleated giant cells that mediate bone resorption. Osteocytes, the most abundant bone cell type, are mature osteoblasts embedded within cortical bone. These cells act as mechanosensors, detecting mechanical strain and transmitting signals that regulate bone remodeling.

Mechanical loading is believed to initiate remodeling through osteocyte signaling, which activates osteoblasts.[37][38] Activated osteoblasts secrete signaling molecules that promote osteoclast differentiation and activation.[39] Among these cytokines and growth factors, the receptor activator of nuclear factor-κ B ligand (RANKL) plays a central role. RANKL exists as both a transmembrane protein and a soluble molecule released into the bone microenvironment.[40]

RANKL binds to its receptor RANK on osteoclast precursors, triggering osteoclastogenesis and stimulating osteoclast activity.[41] Osteoblasts also produce osteoprotegerin (OPG), a decoy receptor that binds RANKL and prevents its interaction with RANK. The RANK-RANKL-OPG axis constitutes a key regulatory pathway in bone metabolism.[42][43][44]

The Wnt-β-catenin signaling pathway serves as a key regulator of bone remodeling. Activation occurs when Wnt proteins bind to their coreceptors, low-density lipoprotein receptor-related proteins 5 and 6 (LRP5, LRP6).[45][46] This interaction, together with binding to the Frizzled receptor, stabilizes β-catenin and promotes its translocation to the nucleus, where it drives the transcription of genes that support osteoblast proliferation, differentiation, and survival.[47]

The pathway also enhances OPG expression, thereby inhibiting osteoclastogenesis and reducing bone resorption.[48][49] Sclerostin, the product of the SOST gene, is a glycoprotein secreted by osteocytes that binds to LRP5 and LRP6, suppressing Wnt signaling and inhibiting bone formation.[50][51] Another inhibitor, dickkopf 1 (Dkk1), similarly binds to LRP5 and LRP6, blocking the Wnt pathway and decreasing osteoblastic activity.[52]

Histopathology

Histologic examination demonstrates markedly thinned trabeculae, reduced osteon size, and enlarged Haversian and marrow spaces.[53] These changes reflect disrupted bone microarchitecture, resulting in reduced mechanical strength and increased fracture susceptibility.

History and Physical

A comprehensive history and physical examination should identify risk factors associated with secondary bone loss. Social history must include assessment of smoking habits and chronic alcohol intake. Family history of osteoporosis should be documented. Inquiry regarding previous fractures is essential, particularly those resulting from low-energy or ground-level falls, and any fracture sustained after the age of 40. Evaluation of physical activity level provides additional insight into mechanical loading status and overall bone health.

Physical examination findings are often unremarkable, except in advanced disease. In individuals without identifiable risk factors, most clinicians recommend screening with DXA in women approaching menopause or age 65, and in men at age 70. The U.S. Preventive Services Task Force has not established official screening guidelines for men, and population-wide osteoporosis screening has not been systematically implemented.

Particular attention should be directed toward patients who sustain fragility fractures, with early follow-up by an appropriate specialist strongly recommended. Although no standardized postfracture follow-up protocol has been established, automated follow-up systems and fracture liaison services have emerged as effective strategies to address the historically low follow-up rates, reported to range from 1% to 10%.

Women with normal DXA findings generally do not require repeat scanning, as evidence indicates that most do not progress to osteoporosis. Some experts support follow-up DXA assessment after initiation of therapy. However, this practice remains controversial because available data demonstrate that repeat scans seldom result in management changes or treatment modification.

Evaluation

Imaging

The WHO designates the DXA scan as the gold standard for evaluating BMD.[54] This modality employs a single x-ray beam to quantify calcified tissue within specific skeletal regions, providing measurements with a precision of 1% to 2%.[55] DXA scanning offers the highest diagnostic accuracy with minimal radiation exposure. Standard evaluation sites include the lumbar spine (L1 to L4), the hip (femoral neck, trochanteric, and intertrochanteric regions), and the wrist. The reported BMD represents an absolute, patient-specific value derived from these anatomic regions.[56]

DXA results include both a T-score and a Z-score. The T-score, expressed in standard deviations, reflects the difference between the patient’s measured BMD and the mean BMD of healthy young adults, typically 30-year-old women. A normal T-score is defined as within 1 standard deviation of the young adult mean, whereas scores between -1 and -2.5 indicate osteopenia, and scores below -2.5 indicate osteoporosis. The Z-score, also expressed in standard deviations, compares the patient’s BMD to that of an age-matched reference group. The Z-score is particularly relevant in younger individuals when secondary osteoporosis is suspected. A value less than -2.0 should prompt a comprehensive evaluation for secondary causes of bone loss.[57]

Fracture Risk Assessment Scoring

The WHO developed the Fracture Risk Assessment Tool (FRAX) to estimate the 10-year probability of sustaining a hip or other major osteoporotic fracture.[58] Major osteoporotic fractures include those involving the spine, wrist, distal forearm, and proximal humerus.[59] The tool comprises 12 variables, each weighted according to its relative contribution to future fracture risk.[60] Parameters include age, sex, personal history of fracture, low BMI, glucocorticoid use, secondary osteoporosis, parental history of hip fracture, smoking status, and alcohol intake.

An optional input for femoral neck BMD from a prior DXA scan may be incorporated to enhance accuracy.[61] Country- and ethnicity-specific versions are available to adjust for regional variations in fracture and mortality rates.[62][63][64] FRAX assessment is intended for adults aged 40 or older.[65]

The FRAX score is particularly valuable in evaluating patients with osteopenia, as most fragility fractures occur within this group rather than in those with established osteoporosis. Although fracture risk correlates with declining BMD, the predominance of fractures in osteopenic patients underscores the need for additional risk stratification.[66] Clinicians utilize the FRAX score to identify osteopenic patients who exceed treatment thresholds, guiding pharmacologic intervention. A 10-year risk of hip fracture of 3% or greater, or a 10-year risk of major osteoporotic fracture of 20% or higher, indicates a sufficiently elevated risk to warrant pharmacotherapy.[67]

Trabecular Bone Score

The trabecular bone score (TBS) provides a qualitative assessment of bone structural integrity, whereas BMD offers a quantitative measure of the same property. TBS is derived indirectly from lumbar spine DXA images using specialized software to evaluate trabecular microarchitecture.[68] This tool cannot replace BMD for the diagnosis of osteopenia or osteoporosis but serves as a complementary parameter in the overall assessment of skeletal health.

TBS enhances fracture risk prediction independent of BMD.[69] The International Society for Clinical Densitometry and the American Association of Clinical Endocrinology recommend the use of this adjunctive tool in individuals aged 40 years or older.[70] In cases of secondary osteoporosis, TBS can detect degraded bone microarchitecture not captured by BMD, prompting earlier or more aggressive intervention.[71] Incorporating TBS-adjusted FRAX probabilities further refines fracture risk prediction compared with FRAX alone.[72] TBS is particularly valuable in conditions where BMD underestimates fracture risk, including hyperparathyroidism, diabetes, chronic kidney disease, rheumatoid arthritis, obesity, and glucocorticoid use.[73]

Laboratory Evaluation

Standard laboratory evaluation includes serum calcium, phosphorus, albumin, renal function tests, and 25-hydroxyvitamin D levels. Further diagnostic testing may be indicated when secondary causes of osteoporosis are suspected.[74] Additional studies include alkaline phosphatase, liver function tests, parathyroid hormone, thyroid function tests, celiac serology, hormonal assays for hypogonadism, prolactin, magnesium, rheumatoid factor, serum or urine protein electrophoresis, and 24-hour urine collection for calcium, creatinine, and cortisol.

Bone Turnover Markers

The routine measurement of bone turnover markers (BTMs) is controversial. BTMs are not indicated for diagnosing low bone mass. However, these markers are useful for monitoring treatment response and adherence in osteoporosis management. BTMs may also assist in identifying secondary causes of bone loss, such as malabsorption.[75][76]

The American Association of Clinical Endocrinology recommends measuring serum procollagen type I N-terminal propeptide, a marker of bone formation, and serum C-terminal telopeptide of type I collagen, a marker of bone resorption. Antiresorptive therapy produces a marked reduction in levels of C-terminal telopeptide of type I collagen, whereas anabolic therapy increases concentrations of procollagen type I N-terminal propeptide. Monitoring is typically performed every 1 to 2 years.[77]

BTM testing is limited by substantial biological and preanalytical variability. Comorbid conditions such as chronic kidney disease can influence results by altering clearance. In addition, BTMs lack diagnostic specificity and sensitivity, and their clinical utility remains constrained by the absence of standardized assay methods.[78]

Treatment / Management

The primary management approach for patients with osteopenia emphasizes early education on strategies to achieve and maintain optimal bone mass. Comprehensive counseling should address social, environmental, and lifestyle risk factors that adversely affect bone health.

Lifestyle Modifications

Calcium homeostasis becomes impaired after menopause, leading to increased total body calcium loss, which reflects a relative predominance of bone resorption over bone formation.[79][80] Aging is associated with deficits in intestinal absorption and renal calcium handling, both of which contribute to decreased calcium levels.[81] Reduced cutaneous vitamin D synthesis further aggravates this imbalance, resulting in compensatory hyperparathyroidism. Increasing calcium intake can help attenuate bone loss, with a recommended daily intake of 1,200 to 1,500 mg after menopause and in later life.[82][83]

Advancing age also increases the risk of vitamin D deficiency due to reduced cutaneous synthesis, lower dietary intake, decreased intestinal absorption, and diminished sun exposure.[84] Vitamin D deficiency predisposes to bone loss and fragility fractures.[85][86][85] Maintaining normal vitamin D levels supports bone health and mitigates accelerated bone loss. Vitamin D supplementation reduces fragility fracture risk in older, institutionalized individuals but not in healthy, community-dwelling adults.[87][88][89]

Physical activity, including aerobic and resistance training, significantly improves BMD and overall quality of life.[90][91] Low-impact activities such as tai chi and yoga enhance balance and flexibility.[92][93] High-intensity exercise produces superior gains in bone density compared with low- or moderate-intensity regimens.[94] Progressive weight-bearing and resistance training stimulate bone formation and reduce fracture risk.[95][96] The Lifting Intervention for Training Muscle and Osteoporosis Rehabilitation (LIFTMOR) trial demonstrated the positive effects of high-intensity, heavy-load resistance training on bone health.[97]

Fall Prevention 

Falls, most of which occur indoors, account for more than 90% of hip fractures and nearly all distal radius fractures. Although evidence regarding the effectiveness of exercise programs and physical therapy interventions in older adults is mixed, particularly in reducing falls and subsequent fragility fractures, several studies support multimodal approaches for improved outcomes. Regular exercise, combined with preventive measures such as removing loose carpets, limiting the use of sedatives and sleep aids, and correcting visual impairment, has been associated with lower fall rates among community-dwelling older adults.[98]

Pharmacotherapy Recommendations 

Consensus supports pharmacologic intervention for individuals with a history of fragility fractures involving the proximal hip, vertebrae, wrist, or proximal humerus, irrespective of BMD. Pharmacologic treatment is also indicated for those with osteopenia, defined by a T score between -1.0 and -2.5, when the FRAX score indicates a 10-year risk of 3% or greater for hip fracture or 20% or greater for major osteoporotic fracture. Individuals with osteoporosis, defined by a T score of -2.5 or lower, likewise meet the criteria for pharmacologic therapy. Pharmacologic management of osteopenia and osteoporosis involves agents that act through either antiresorptive mechanisms, which inhibit bone resorption, or anabolic mechanisms, which stimulate bone formation.

Antiresorptive therapy

Antiresorptive drugs inhibit osteoclastic activity, thereby slowing bone loss. These agents include bisphosphonates and denosumab, with bisphosphonates being the most widely prescribed class due to their established efficacy and favorable safety profile.

Bisphosphonates are 1st-line agents for managing osteopenia and osteoporosis. Aminobisphosphonates, which are approved by the U.S. Food and Drug Administration (FDA), inhibit farnesyl pyrophosphate synthase in the mevalonate pathway, disrupting protein prenylation essential for osteoclast function and promoting osteoclast apoptosis.[99] These agents bind directly to hydroxyapatite, are internalized by osteoclasts, and act intracellularly to suppress bone resorption.

Oral bisphosphonates are typically administered for 5 years (FLEX trial) and intravenous formulations for 3 years (HORIZON-PFT trial) before initiating a drug holiday, which may be extended to 10 and 6 years, respectively, in high-risk individuals.[100][101][100] Alendronate (70 mg weekly or 10 mg daily) reduces vertebral, hip, and nonvertebral fractures by 44%, 40%, and 17%, respectively (FIT trial).[102] Ibandronate (150 mg orally monthly or 3 mg intravenously every 3 months) reduces vertebral fractures by 31% but has limited efficacy for hip and nonvertebral fractures (MOBILE study, DIVA trial).[103][104][103] Risedronate (35 mg weekly, 5 mg daily, or 150 mg monthly) reduces vertebral, hip, and nonvertebral fractures by 36%, 26%, and 20%, respectively (VERT-MN trial).[105][106] Zoledronic acid (5 mg intravenously once yearly) reduces vertebral, hip, and nonvertebral fractures by 56%, 42%, and 18%, respectively (HORIZON trial).[107]

According to Endocrine Society guidelines, ibandronate and risedronate exhibit less persistent residual effects after discontinuation than alendronate and zoledronic acid, with benefits diminishing more rapidly. When a drug holiday is considered after 3 to 5 years of ibandronate, the interruption should not exceed 6 months in patients at continued fracture risk. Bisphosphonates are contraindicated in individuals with an estimated glomerular filtration rate below 30 to 35 mL/minute/1.73 m², hypocalcemia, esophageal abnormalities such as stricture or achalasia, or hypersensitivity to the drug. These medications are generally well-tolerated, with serious adverse events occurring at rates comparable to placebo over 3 to 5 years of use.[108]

Oral formulations may cause mild upper gastrointestinal symptoms, including dyspepsia and acid reflux, while severe esophageal complications are rare. Zoledronic acid commonly causes transient flu-like symptoms, including fever, myalgia, and arthralgia, within a few days of infusion, affecting 15% to 30% of individuals. Osteonecrosis of the jaw occurs in 0.01% to 0.3% of users, and atypical femur fractures occur in 2.5 to 13 per 10,000 patient-years, both risks declining rapidly after drug discontinuation.[109][110]

Denosumab is a monoclonal immunoglobulin G2 antibody that produces a potent but reversible inhibition of RANKL, blocking the RANK-RANKL interaction essential for osteoclast formation and activity, and inducing osteoclast apoptosis. This medication increases BMD more than bisphosphonates at all major skeletal sites over 12 to 24 months, though both classes achieve comparable fracture risk reduction.[111][112]

The effects of denosumab reverse rapidly upon discontinuation, with a marked rise in bone resorption and vertebral fracture risk unless promptly followed by bisphosphonate therapy.[113] Consequently, the drug is reserved for patients who cannot tolerate or do not respond to bisphosphonates, including those with advanced chronic kidney disease (estimated glomerular filtration rate below 30 mL/minute/1.73 m²) or dialysis dependence. Calcium levels must be monitored closely due to an increased risk of hypocalcemia. Rare adverse effects include osteonecrosis of the jaw and atypical femur fractures, both of which are associated with prolonged use.[114]

Hormone-based and biologic agents

Estrogen replacement therapy is FDA-approved for the prevention of osteoporosis but not for its treatment. This intervention reduces the risk of vertebral, hip, and nonvertebral fractures by 20% to  40% and increases BMD at the spine and hip in postmenopausal women, regardless of baseline fracture risk. Even low doses, such as 0.014 mg/day transdermal estradiol or 0.25 mg/day oral estradiol, confer bone health benefits, although fracture prevention at these doses has not been studied.[115][116] Patient selection should focus on women younger than 60 or within 10 years of menopause onset, those experiencing significant vasomotor symptoms, individuals at low risk for serious adverse effects (venous thromboembolism, stroke, cardiovascular events, or breast cancer), and those with osteopenia or low bone mass.

Raloxifene, a selective estrogen receptor modulator, acts as an agonist on bone estrogen receptors to reduce osteoclast resorption while exerting antagonist effects on breast and uterine tissue. Administered orally at 60 mg once daily, this drug reduces vertebral fractures by 30% to 40% but does not significantly affect nonvertebral or hip fractures, making it particularly suitable for patients with low spinal BMD but preserved hip BMD. Raloxifene is also FDA-approved for the prevention of invasive breast cancer in high-risk postmenopausal women.[117] Common adverse effects include hot flashes, arthralgias, leg cramps, and flu-like symptoms, with increased risks of venous thromboembolism and stroke.[118] Therapy duration is individualized based on vertebral fracture risk, and drug holidays are not recommended.

Anabolic agents, including teriparatide (recombinant parathyroid hormone), abaloparatide (recombinant parathyroid hormone-related peptide), and romosozumab (monoclonal antibody against sclerostin), stimulate bone formation and are reserved for individuals with osteoporosis and a history of fragility fracture.[119]

Differential Diagnosis

Secondary causes of low bone mass and fragility fractures extend beyond primary osteoporosis and require careful consideration in clinical assessment. The following conditions and scenarios are included because they either directly disrupt bone metabolism or increase fracture risk through systemic, metabolic, or environmental mechanisms:

• Osteomalacia
• Malignancy
• Paget disease of bone
• Multiple myeloma
• Hyperparathyroidism
• Hyperthyroidism
• Renal osteodystrophy
• Abuse of older persons

Clinicians should maintain a high index of suspicion for these conditions when evaluating patients with low bone mass or atypical fractures. Targeted history, laboratory testing, and imaging are essential to differentiate among these etiologies and guide appropriate management.

Prognosis

Individuals with osteopenia or low bone mass have a better prognosis when fragility fractures are prevented through lifestyle interventions, including high-intensity resistance training, and, in high-risk populations, pharmacotherapy. The prognosis worsens for patients who have sustained a fragility fracture, with increased mortality, functional impairment, and reduced quality of life.[120][121] Therefore, timely screening and early implementation of preventative measures are crucial.

Complications

Fragility fractures resulting from low bone mass can lead to significant clinical consequences. Sequelae include pain and functional impairment, as fractures of the hip, spine, and wrist often produce both acute and chronic pain, reduced mobility, and difficulty performing daily activities.[122][123] Loss of independence is common, as more than half of individuals with hip fractures are unable to resume independent living, with many requiring long-term nursing home care.[124]

Vertebral compression fractures may result in spinal deformity, height loss, compromised pulmonary function, and chronic back pain.[125][126][127] Fragility fractures also substantially increase the risk of subsequent fractures, with individuals experiencing a 2-fold or greater risk regardless of BMD, particularly in those with osteopenia. Mortality risk doubles in the 1st year following a fracture, remaining elevated for up to 5 years and, in some cases, extending to 10 years.[128][129][128] These fractures ultimately contribute to a reduced quality of life.

Deterrence and Patient Education

Osteopenia, or low bone mass, is defined as a reduction in BMD below normal reference values that does not meet the diagnostic threshold for osteoporosis. BMD is measured using DXA scans. Screening is generally initiated at age 65 for women, but earlier evaluation is warranted in individuals with high-risk factors for accelerated bone loss.

Individuals with osteopenia should undergo fracture risk assessment using FRAX, as the majority of fragility fractures occur in this population rather than in those with osteoporosis. Patients identified as high risk for hip or major osteoporotic fractures receive pharmacotherapy, while individuals with low or moderate fracture risk typically do not require medication. Lifestyle interventions remain essential, including adequate calcium and vitamin D intake. High-intensity resistance training has been consistently shown to improve BMD and reduce fracture risk.

Enhancing Healthcare Team Outcomes

Osteopenia and osteoporosis, along with their associated complications, contribute substantially to patient morbidity and mortality and impose a considerable financial and resource burden on the healthcare system. Prevention of osteopenia is therefore a primary goal, optimally achieved through an interprofessional team approach emphasizing patient education. All clinicians should inform patients about the risks associated with low bone mass, while nurse practitioners, pharmacists, and primary care providers should promote a calcium-rich diet. Patients should also be counseled to engage in regular exercise, cease smoking, and abstain from alcohol. Pharmacists play a critical role in educating patients about bisphosphonates, including their benefits and potential adverse effects.

Bone densitometry should be performed in all postmenopausal women, with patients educated on its clinical value. Healthcare providers must coordinate to ensure individuals diagnosed with a fragility fracture receive prompt follow-up with clinicians experienced in managing low BMD. This area has received increasing attention in the literature, as documented follow-up rates have historically been low, ranging from 5% to 15%. The overarching goal is to optimize interprofessional care, reduce the risk of subsequent fractures and surgeries, and minimize morbidity and mortality.[130]

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Disclosure: Matthew Varacallo declares no relevant financial relationships with ineligible companies.

Disclosure: Travis Seaman declares no relevant financial relationships with ineligible companies.

Disclosure: Jagmohan Jandu declares no relevant financial relationships with ineligible companies.

Disclosure: Jasleen Kaur declares no relevant financial relationships with ineligible companies.