Individualized Fracture Prevention for Postmenopausal Women with Osteopenia

Abstract

Osteopenia—defined by a bone mineral density T-score between −1.0 and −2.5—is more common than osteoporosis and accounts for most fragility fractures in postmenopausal women. Approximately 50% of Korean women aged ≥ 50 years have osteopenia. Despite this high prevalence, optimal therapeutic strategies remain unclear. This review summarizes the clinical significance and management of osteopenia. Clinical practice often categorizes osteopenia into mild, moderate, and severe based on specific T-score ranges. Studies indicate that women transitioning from normal or moderate osteopenia to lower bone density experience more fractures. One study reported that approximately 10% of women with normal BMD or osteopenia progressed to osteoporosis, mostly from moderate to severe osteopenia groups. Fracture risks, particularly for hip and vertebral fractures, are elevated mainly in moderate to severe osteopenia. The National Osteoporosis Foundation and the American Association of Clinical Endocrinologists incorporate FRAX^® scores alongside T-scores and clinical history to guide pharmacological intervention. Accordingly, South Korean guidelines classify fracture-risk groups as low, moderate, high, or very high, allowing treatment of patients with osteopenia in the high-risk categories. Evidence supporting medications for fracture prevention remains limited. However, growing interest in preventing fractures has directed the ongoing studies to evaluate various drugs. Food and Drug Administration-approved treatments include menopausal hormone therapy, bisphosphonates, and selective estrogen receptor modulators. To reduce fractures in postmenopausal women, treatment should not be restricted to osteoporosis alone. Women with moderate to severe osteopenia may also benefit from medications used for osteoporosis. Clinicians should assess individual fracture risks and select preventive treatments based on risk level, fracture site, menopausal symptoms, patient preference, and cost-effectiveness.

INTRODUCTION

Osteopenia, defined by a bone mineral density (BMD) T-score between −1.0 and −2.5, is significantly more prevalent than osteoporosis and accounts for the majority of fragility fractures in postmenopausal women. Although the incidence of fractures attributable to osteopenia is considerable, the most effective therapeutic approaches for this condition continue to be the subject of ongoing debate. Given the rapidly aging population in Korea, the social burden of osteopenia-related fractures is expected to increase.

Accordingly, it is necessary to set the goal of treatment in prevention of fracture. With considering clinical risk factors and cost-effectiveness, establishment of appropriate BMD thresholds for initiate treatment even in osteopenia patients and the evaluation of individualized fracture risk using tools such as FRAX^® are important [1,2].

This review aims to summarize current evidence regarding the clinical significance and management of osteopenia.

PREVALENCE & FRACTURE RISK

Recent nationwide statistics from the Korea National Health and Nutrition Examination Survey (KNHANES) report that 48.9% of women aged 50 and above have osteopenia. The high prevalence of osteopenia highlights the importance of early detection and management strategies to prevent progression to osteoporosis and related fractures [3].

The NORA (National Osteoporosis Risk Assessment) study is one of the largest, prospective observational study conducted in the United States that evaluated how BMD correlates with fracture risk among postmenopausal women. Although the risk of individual fractures was higher in the osteoporosis (T-score ≤ -2.5) group, most fractures occurred in women with osteopenia. This was because the osteopenia group was a large proportion of the total population. Notable, only 6.4% of women had osteoporosis; despite their greater personal risk, these women contributed to just 18% of all osteoporotic fractures and 26% of hip fractures. By contrast, 82% of fractures were seen in women with T-scores above -2.5, most of which occurred in women with osteopenia [4,5,6].

In a large population-based retrospective cohort study that analyzed fracture risk in South Korea, among postmenopausal women, the 10-year cumulative incidence rates of any fracture were 31.1% for those with normal BMD, 37.5% for those with osteopenia, and 44.3% for those diagnosed with osteoporosis. Similarly, the 10-year cumulative incidence of vertebral fracture was greater in osteopenic group compared to women with normal bone density (10.9% vs. 6.5%), a pattern mirrored in hip fractures (2.2% vs. 1.9%) and non-hip, non-vertebral fractures (30.7% vs. 26.5%). Although the cumulative fracture rate was highest among those with osteoporosis, this difference compared to the osteopenic group was not marked [7]. Table 1 [7] presents the overall fracture risk according to osteoporosis treatment status during the follow-up period. Women with osteoporosis who initiated an osteoporosis treatment during follow-up had a lower 10-year cumulative incidence of fracture compared to those who remained untreated. A comparable trend was found among women with osteopenia, where the 10-year cumulative fracture rate was notably lower in those who received osteoporosis treatment versus those who did not (30.3% compared to 37.8%).

Table 1. Risk of overall fracture stratified by the use of osteoporosis treatment during the follow-up in subjects with osteopenia or osteoporosis versus subjects with normal BMD.

Stratification		No. of subject	No. of event	PY at risk	10-Year cumulative incidence (%)	Incidence rate per 100 PY (95% CI)a	Crude HR (95% CI)	Adjusted HR (95% CI)b
With any osteoporosis treatment use during follow-upc
	Normal	8,067	1,359	46,574	26.5	2.92 (2.77–3.07)	Ref (1.00)	Ref (1.00)
	Osteopenia	33,657	6,191	181,420	30.3	3.41 (3.33–3.50)	1.19 (1.12–1.26)	1.21 (1.14–1.29)
	Osteoporosis	57,120	13,178	270,059	38.3	4.88 (4.80–4.96)	1.75 (1.66–1.86)	1.85 (1.74–1.95)
Without any osteoporosis treatment use during follow-up
	Normal	48,122	8,445	215,596	29.4	3.92 (3.84–4.00)	Ref (1.00)	Ref (1.00)
	Osteopenia	85,801	20,032	364,061	37.8	5.50 (5.43–5.58)	1.40 (1.37–1.44)	1.43 (1.40–1.47)
	Osteoporosis	38,430	12,466	154,028	48.9	8.09 (7.96–8.23)	2.06 (2.00–2.12)	2.17 (2.11–2.23)

BMD: bone mineral density, PY: person-years, CI: confidence interval, HR: hazard ratio.

^aIncidence rate per 100 person-years = (number of incident fracture events/person-years at risk) × 100. ^bAdjusted for income, smoking, alcohol consumption, body mass index, comorbidities (thyroid dysfunction, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, hypertension, myocardial infarction, heart failure, diabetes mellitus, dyslipidemia, stroke, chronic kidney disease, and gastrointestinal disorders), and comedications (thyroid hormones, calcium and vitamin D, anticonvulsants, proton pump inhibitors, selective serotonin reuptake inhibitors, and benzodiazepines). ^cOsteoporosis treatment status was ascertained between the index BMD screening date and end of follow-up (fracture occurrence, censoring event, or study end date).

Reproduced from the article of Baek et al. (Endocrinol Metab 2021; 36: 1178-88) [7].

So interventions based solely on the osteoporosis threshold (T-score ≤ -2.5) are insufficient. Effective fracture risk reduction strategies must consider both BMD and additional clinical risk factors to identify high-risk individuals among those with osteopenia.

CLINICAL SUBCLASSIFICATION

While although the official World Health Organization (WHO) classification did not subdivide within osteopenia range, clinical practice and research have increasingly adopted informal categories to better stratify fracture risk. Several studies and guidelines have proposed dividing osteopenia into subgroups such as mild, moderate, and severe, based on specific T-score thresholds. For example, some researchers classify mild osteopenia as T-scores between −1.0 and −1.49, moderate osteopenia as −1.5 to −1.99, and severe osteopenia as −2.0 to −2.49. Others use slightly different cutoffs, such as mild-to-moderate osteopenia for T-scores above −2.0 and severe osteopenia for T-scores between -2.49 and −2.0 [8,9]. These subdivisions help clinicians identify individuals at higher risk of rapid bone loss, progression to osteoporosis, or future fractures, and may influence the frequency of monitoring or the decision to initiate pharmacological therapy.

According to a study that subdivided osteopenia into mild, moderate, and severe and followed up BMD and fracture, women experiencing a transition from normal BMD or moderate osteopenia to lower BMD categories during the observation period sustained significantly more fractures than those who started with moderate or severe osteopenia [9]. Approximately 10.2% of patients progressed to osteoporosis during the study period; notably, 90.5% of these individuals had moderate or severe osteopenia at baseline (Table 2) [9]. During a mean follow-up of 9.6 years, women presenting with osteopenia at baseline experienced higher incidences of overall and intermediate fractures relative to individuals with normal baseline BMD. However elevated risks for hip, vertebral, minor site, and major site fractures were confined to the subgroup with moderate to severe baseline osteopenia (Table 2) [9].

Table 2. Changes related to transition in women with osteopenia compared with those with normal BMDs at baseline and subsequent fracture occurrence.

Initial DXA score		Normal (n = 396)	Mild (n = 277)	Moderate (n = 281)	Severe (n = 196)
Transition to lower categories (n = 399)		101 (25.5)	104 (37.5)	117 (41.6)	77 (39.3)
	P	-	0.001	< 0.001	0.001
Transition to osteoporosis (n = 116)		1 (0.01)	10 (3.6)	28 (9.9)	77 (39.3)
	P a	-	< 0.001	< 0.001	< 0.001
Individuals fracturing (n = 199)		38 (9.6)	47 (17.0)	59 (21.0)	55 (28.1)
	P	-	0.005	< 0.001	< 0.001
Total fractures (n = 239)		43 (10.9)	55 (19.5)	74 (26.3)	67 (34.2)
	P	-	0.001	< 0.001	< 0.001
Major fractures (n = 64)		12 (3.0)	10 (3.6)	22 (7.83)	20 (10.2)
	P	-	0.68	0.005	< 0.001
Hip fractures (n = 22)		2 (0.5)	4 (1.44)	7 (2.49)	9 (4.59)
	P	-	0.24	0.04	0.001
Vertebral fractures (n = 31)		7 (1.77)	4 (1.44)	12 (4.27)	8 (4.08)
	P	-	1.00	0.052	0.092
Intermediate fractures (n = 127)		24 (6.06)	34 (12.3)	38 (13.9)	30 (15.3)
	P	-	0.005	0.001	< 0.001
Minor fractures (n = 48)		7 (1.76)	11 (3.97)	13 (4.63)	17 (8.67)
	P	-	0.081	0.030	< 0.001

Data are presented as number (%). Values in parentheses represent the percentage of the total population in each category.

BMD: bone mineral density, DXA: dual-energy X-ray absorptiometry, -: not available.

^aFisher exact test.

Reproduced from the article of Pfister et al. (South Med J 2016; 109: 118-23) [9] with original copyright holder’s permission.

RISK ASSESSMENT

Fracture risk assessment tool, FRAX^®

The FRAX^® tool, which is most commonly used for risk assessment, was developed based on population-based cohort studies for each race and assess individualized risk by incorporating clinical risk factors. The FRAX^® tool calculates the 10-year probability of hip fracture as well as the 10-year risk of a major osteoporotic fracture, which encompasses clinical fractures of the spine, proximal humerus (shoulder), distal forearm, and hip. The tool incorporates the following variables as risk factors: Age, sex, body weight, height, history of prior fractures, parental history of hip fracture, current tobacco smoking, history of systemic glucocorticoid therapy, presence of rheumatoid arthritis, secondary causes of osteoporosis, alcohol intake of three or more units daily (with one unit defined as 8–10 grams of alcohol), optional inclusion of femoral neck BMD (if available) [10].

It should be noted that FRAX^® only reports risk for hip fractures and major fractures, which account for approximately half of all fragility fractures, potentially underestimating fracture risk. Furthermore, FRAX^® does not account for other factors that increase fracture risk, such as falls, high fall risk, multiple osteoporosis-related fractures, recent fractures, and patients with lumbar spine BMD significantly lower than femoral neck BMD. Therefore, individual risk assessments should consider these factors [11].

Therapeutic intervention threshold

Previously, the National Osteoporosis Foundation (NOF) developed treatment thresholds by combining BMD measured at the hip with clinical risk factors for fracture (e.g., prior fracture as an adult, family history of fracture, body weight < 127 pounds, cigarette smoking) [12]. According to this recommendation, women with a T-score of −2.0 or less or −1.5 or less with at least one risk factor should be considered for treatment [12]. In the group of women meeting the NOF treatment guidelines, osteoporotic and hip fracture rates were relatively low at 24.7 and 5.1 per 1,000 person-years, respectively, while the incidence of all osteoporotic and all hip fracture was high at 45% and 53% respectively [5]. Application of this threshold resulted in 22.6% of the NORA cohort being classified as subjects to be treated, that increased compared to when osteoporosis was considered as a subject of treatment.

In 2014, the NOF recommended initiating pharmacologic therapy in individuals with osteopenia at the femoral neck, total hip, or lumbar spine as identified by dual-energy X-ray absorptiometry (DXA) if their 10-year probability of hip fracture is ≥ 3% or if their 10-year probability of a major osteoporosis-related fracture is ≥ 20%, according to the US-adapted WHO FRAX^® model [13,14].

The 2020 American Association of Clinical Endocrinologists (AACE) guidelines stated the criteria for drug treatment as follows [11]:

a. Individuals who have a T-score between −1.0 and −2.5 at the spine, femoral neck, total hip, or the 1/3 radius and have fragility fracture of the hip or spine.

b. Patients whose T-score is equal to or less than −2.5 in the spine, femoral neck, total hip, or 1/3 radius.

c. Patients who have a T-score between −1.0 and −2.5 in the spine, femoral neck, total hip, or 1/3 radius, and a 10-year probability of major osteoporotic fracture by FRAX^® (or trabecular bone score [TBS]-adjusted FRAX^®, if available) ≥ 20%, or a 10-year probability of hip fracture ≥ 3% (in the US) or exceeding country-specific thresholds in other countries or regions.

Evidence-based recommendations of South Korea

According to the clinical practice guidelines for osteoporosis in South Korea, FRAX^® can be used for the purpose of selecting patients to be treated who do not receive drug treatment. Based on the fracture history, bone density T-score, and the fracture risk within 10 years on FRAX^®, the fracture risk group is classified into a low risk, moderate risk, high risk, and very high risk for treatment. Even osteopenia is subject to osteoporosis drug treatment in high-risk groups or higher (Table 3) [15].

Table 3. Category of fracture risk groups.

Risk category	Inclusion criteria
Low risk	Must meet all of the following
		No history of fragility fractures (hip, vertebral, or other major fractures)
		Bone mineral density T-score ≥ –1.0
		FRAX® 10-year probability of major osteoporotic fracture < 20% and hip fracture < 3%
Moderate risk	Must meet all of the following
		No history of fragility fractures (hip, vertebral, or other major fractures)
		Bone mineral density T-score greater than −2.5 and less than −1.0
		FRAX® 10-year probability of major osteoporotic fracture < 20% and hip fracture < 3%
High risk	Meets any of the following
		Previous fragility fracture (hip, vertebral, or other major fracture)
		Bone mineral density T-score ≤ –2.5
		FRAX® 10-year probability of major osteoporotic fracture ≥ 20% or hip fracture ≥ 3%
Very high risk	Meets any of the following
		Fragility fracture (hip, vertebral, or other) within the last 12 months
		Fracture occurring while on anti-osteoporotic treatment
		Multiple fractures
		Fracture while receiving medications that negatively affect bone (e.g., glucocorticoids)
		Bone mineral density T-score < –3.0
		Severe trauma or high-risk fall associated with fracture
		FRAX® 10-year probability of major osteoporotic fracture ≥ 30% or hip fracture ≥ 4.5%

Reproduced from the Korean Academy of Medical Sciences. Evidence-based recommendations for osteoporosis in primary care. 2024 [15].

TREATMENT

To date, clinical evidence on the benefits of osteoporosis treatments for fracture prevention is insufficient and conflicting. However, as interest in fracture prevention has recently increased, studies related to the preventive effect of each drug are also being conducted. Table 4 [11] lists Food and Drug Administration (FDA)-approved drugs for the prevention and treatment of osteoporosis.

Table 4. Drugs approved by the U.S. Food and Drug Administration for prevention and treatment of postmenopausal osteoporosis^a.

Drug	Postmenopausal osteoporosis
	Prevention	Treatment
Abaloparatide (Tymlos)	-	80 µg SQ daily
Alendronate (Fosamax)	5 mg PO daily	10 mg PO daily
	35 mg PO weekly	70 mg PO weeklyb
		70 mg + Dc
Calcitonin (Miacalcin, Fortical)	-	200 IU intranasally once daily or 100 IU SQ qod
Denosumab (Prolia)	-	60 mg SQ every 6 months
Estrogen (multiple formulations; estrogenbazodoxifene)	Multiple regimens	-
Ibandronate (Boniva, generic form)	2.5 mg PO daily	2.5 mg PO daily
	150 mg PO monthly	150 mg PO monthly
		3 mg IV every 3 months
Raloxifene (Evista)	60 mg PO daily	60 mg PO daily
Risedronate (Actonel, Atelvia, generic form)d	5 mg PO daily	5 mg PO daily
	35 mg PO weekly	35 mg PO weekly
	150 mg PO monthly	150 mg PO monthly
Romosozumab (Evenity)	-	210 mg SQ monthly
Teriparatide (Forteo)	-	20 µg SQ daily
Zoledronate (Reclast, generic infusion form)	5 mg IV every 2nd year	5 mg IV once yearly

IV: intravenously, PO: orally, qod: every other day, SQ: subcutaneously, -: not available.

^aPlease review the package inserts for specific prescribing information. ^bFosamax 70 mg is available as both a tablet and a unit dose liquid. Alendronate (generic Fosamax) is available. ^cFosamax Plus D is a tablet containing 70 mg of alendronate and 2,800 IU or 5,600 IU of vitamin D for weekly administration. ^dRisedronate 150 mg once monthly tablet is available.

Reproduced from the article of Camacho et al. (Endocr Pract 2020; 26: 1-46) [11].

Menopausal hormone therapy

Recent findings from the Women’s Health Initiative randomized trial showed a reduction of clinical fractures and hip fractures with hormone therapy (combined estrogen and progestin therapy) in postmenopausal women regardless of baseline fracture risk factors or bone mineral density classification, which suggests that treatment of women with osteopenia reduces fracture risk [16,17].

Bisphosphonates (e.g., alendronate, risedronate, zoledronate)

The effect is greater in those with lower baseline BMD, but significant fracture reduction is still observed among individuals with osteopenia. The all-fracture outcome reached statistical significance, though risk reduction is slightly lower above −2.5 than below. In quintile analysis, efficacy was noted across all BMD groups and all clinical fractures was less certain in the highest BMD quintile (T-score > −1.7) [18]. The efficacy of ibandronate in non-vertebral fractures is uncertain [11].

Selective estrogen receptor modulators

Proven benefit in reducing vertebral fractures in both osteoporosis and osteopenia, but less or unclear effect on non-vertebral and hip fractures, especially in higher BMD (osteopenia) groups [18].

Denosumab

In a large randomized controlled trial, denosumab significantly reduced the risk of new vertebral fractures among all subgroups of postmenopausal women, including those with osteopenia (femoral neck BMD T-score > −2.5). However, the reduction of nonvertebral fracture risk was only statistically significant in women with osteoporosis (T-score ≤ −2.5) and not in those with osteopenia [19]. Other post-hoc analyses have similarly reported mixed conclusions regarding the efficacy of denosumab in reducing non-vertebral fractures [20,21]. Thus, denosumab is effective in lowering vertebral fracture risk for women with osteopenia, but its effect on non-vertebral fracture risk needs further evidence.

Greater fracture risk reductions were observed in patients at moderate-to-high risk, including those with lower BMD typical of osteopenia. Risk reduction was more pronounced at higher baseline FRAX^® probabilities: 11% at 10% probability (P = 0.629), 71% at 20% (P < 0.001), and 50% at 30% (90th percentile, P = 0.001). And enhanced efficacy was also observed in low body mass index (BMI) patients, regardless of prior fractures or secondary osteoporosis [21]. Therefore, patients with elevated FRAX^® risk represent ideal candidates for denosumab therapy.

Anabolic agent

Recent large-scale meta-analyses indicate that anabolic agents, such as teriparatide, abaloparatide, and romosozumab, significantly reduce vertebral and clinical fracture risk not only in patients with osteoporosis but also in those with osteopenia and were generally more effective than bisphosphonates [18,22].

Currently, Korea’s insurance guidelines do not cover osteoporosis treatments in osteopenia unless there are additional risk factors such as previous fractures, long-term steroid use [7]. And recognized non-reimbursable treatments applied in Korea because of their proven effectiveness in preventing postmenopausal osteoporosis include alendronate (5 mg, daily), risedronate, zoledronate, raloxifene, and bazedoxifen [15].

CONCLUSION

To significantly reduce osteoporotic fractures in postmenopausal women, aggressive treatment should not be limited to women with a T-score of -2.5 or lower. More effective treatment efforts are needed for women with moderately low bone mass but who are at high risk for future fractures. In particular, moderate and severe osteopenia have a high risk of transitioning to osteoporosis and overall fracture in the future, so it may be better to consider treatment according to osteoporosis. Therefore, for women with osteopenia, clinician should do risk stratification taking into account individual fracture risk factors, including FRAX^® and consider individualized treatment. And expanding insurance coverage is also necessary to use various drugs for this purpose.

For patients with osteopenia who are at high risk for fracture, it is important to select preventive medications considering the patient’s individual risk level, the site of concern for fracture, presence of menopausal symptoms, preference, and cost-effectiveness. Since most of the osteoporosis treatment RCTs have been conducted on osteoporosis women, more large-scale studies are needed in the future to evaluate the efficacy of reducing fracture risk in women with osteopenia. And also studies focused on benefits and risks of medical treatment among osteopenic individuals are necessary.