Osteoporosis is a treatable and exceedingly underdiagnosed disorder.1,2 Fragility fractures are associated with substantial morbidity and mortality, as well as a notable decline in health-related quality of life, and are a cause of increases in healthcare costs.3–6 In addition, the high risk of subsequent fractures, particularly in the year immediately after the initial fracture, is well-documented.7–10 Despite the many available treatment options, recently published studies indicate that most of the patients with osteoporosis remain untreated.11–13
Evidence-based guidelines were established by a number of organizations to aid physicians in the effective assessment of risk and management of patients with osteoporosis.14–16 The guidelines of the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) were updated in 2020, providing specific criteria for patients at very high risk of osteoporotic fracture.14 In addition to the recency of fractures, multiple fractures, and low bone density, several other factors should be considered in the evaluation of risk. These include fracture incidence while on medications with known adverse effects on bone, a high risk of fall or a history of falls resulting in injury, or the presence of comorbidities associated with increased risk of falls/fractures and indicators of compromised bone quality/healing. In the 2016 version of the guidelines, patients at higher risk of fracture were not defined by specific criteria; however, the recommendations for treating these patients were similar to those described in the 2020 guidelines.
Among drugs approved for the prevention and treatment of osteoporosis, there is strong evidence that teriparatide, abaloparatide (not yet approved in 2016), and romosozumab (not yet approved in 2016) can more rapidly reduce fracture risk. These agents are currently recommended as initial treatment options for patients at very high risk of fracture.14,17–20 In addition, yearly monitoring for treatment response and change in fracture risk are necessary should a modification of the initial management plan be required.14
Recent studies suggest that there is a gap between the recommendations from expert guidelines and the actual observed treatment behaviors and rates from real-world clinical practice settings.11–13,21 In a study using data from Medicare fee-for-service patients, nearly two-thirds of patients with an osteoporotic fracture were neither diagnosed nor treated before the fracture, and one in five were treated.13 Among men, these numbers were more concerning, with most (92.8%) undiagnosed and untreated and approximately one in 20 receiving treatment after the sentinel fracture. The benefits of treatment are well-substantiated for patients at higher risk of fracture.16 Thus, the objective of this study was to document the prevalence of patients who are at very high risk of fracture according to the AACE/ACE guidelines and to evaluate treatment practices for this population specifically.
Methods
Study Design and Population
This was a retrospective observational cohort study using pharmacy and medical claims data, linked to commercial and Medicare medical claims from Symphony Health PatientSource aggregated across multiple payers. Patients with osteoporosis (determined by the presence of a diagnosis code; ICD-9 733.0x; ICD-10 M81.0) who were at very high risk of fracture at any time during the identification period (January 1, 2018, to December 31, 2018) were included in the analysis. No patient's identity or medical records were disclosed for the purposes of this study. Only data deidentified in compliance with 45 CFR 164.514(a)-(c) and accessed using HIPAA-compliant procedures were used.
Patients were required to have 12 months of data availability before and after the point during the identification window, at which they qualified for being at very high risk. Additional pharmacy and medical claims data, available for some patients between September 1, 2011, and August 31, 2020, were also considered for identifying patients' risk-qualifying characteristics and evaluating osteoporosis treatment (Figure 1).
;)
Figure 1: Study time line. AACE = American Association of Clinical Endocrinology; ACE = American College of Endocrinology.
Patients without complete demographic information were excluded. Patients younger than 50 years and patients with conditions contraindicated or associated with warnings and/or precautions noted in the prescribing labels for any of the recommended osteoporosis medications were excluded (except, as noted, when an additional analysis was conducted including patients with gastrointestinal disorders).
Medications for Osteoporosis
The number and proportion of patients treated with any medication for osteoporosis after being designated as very high risk were assessed. Approved medicines for osteoporosis considered for this study included alendronate sodium, alendronate sodium with cholecalciferol, alendronate sodium/cholecalciferol, raloxifene, risedronate sodium, risedronate sodium delayed release, risedronate sodium with calcium, teriparatide, ibandronate sodium (oral and IV), calcitonin, zoledronic acid, denosumab (excluding Xgeva), abaloparatide, and romosozumab.
Identifying Patients at Very High Risk
Eligible patients were determined to be at very high risk of fracture based on the AACE/ACE 2020 guidelines and available risk factor data from Symphony. Data were based on claims for inpatient and outpatient healthcare encounters, and one or more of the following characteristics were required (Supplemental Table 1, https://links.lww.com/JAAOS/A875): (1) a history of fracture while on any osteoporosis therapy; (2) multiple fractures over the observation period; (3) fractures within the past 12 months; (4) fractures while on medication with known adverse effects on bone (eg, long-term glucocorticoids); and/or (5) a history of falls resulting in injury or a comorbidity associated with high risk of falls, fracture, or poor bone quality. A previously validated claims-based algorithm was used to identify case-qualifying osteoporotic fractures.22
Statistical Methods
Patient demographics, medical history (particularly, gastrointestinal disorders), fracture risk factors, and treatment data were summarized descriptively using SAS (v.9.4).
Additional Variables of Interest
It was of interest to further characterize treatment patterns in patients with and without a history of gastrointestinal disorders because gastrointestinal side effects have been associated with oral bisphosphonates.23 Treatment selection for these patients may be affected by this consideration, irrespective of fracture risk status. Therefore, analyses were conducted with and without this subgroup of patients. In addition, separate analyses by sex were conducted.
Results
Of the 10,739,286 patients with osteoporosis, nearly half (5,225,732 [48.7%]) were considered to be at very high risk of fracture based on meeting the qualifying criteria anytime in 2018 and had at least 12 months of data availability before and after the point at which they qualified for being at very high risk. After excluding patients without complete demographic information and those younger than 50 years, the final number of patients included in this analysis was 5,078,111 (Figure 2). The mean age (SD) of patients included in the analyses was 72.7 (7.1) years. Most patients were 65 years or older (4,276,893 [84.2%]) and female (4,417,465 [87.0%]) (Table 1).
Figure 2: Patients at very high risk of fracture according to the American Association of Clinical Endocrinology (AACE)/American College of Endocrinology (ACE) 2020 guidelines and available risk factor data. a Patients with osteoporosis were identified based on having a diagnosis of osteoporosis using available data from Symphony Health PatientSource and were required to have at least 12 months of data before and after being identified as very high risk of fracture. b Met AACE/ACE guidelines for high fracture risk during the identification period (January 1, 2018, to December 31, 2018) and using available data, including a history of fracture while on osteoporosis therapy, multiple fractures over the observation period, fractures within the past 12 months, fractures while on medication with known adverse effects on bone (eg, long-term glucocorticoids), and/or a history of falls resulting in injury or a comorbidity associated with high risk of falls, fracture, or poor bone quality. c May have one or more of any of the risk factors included in the analysis.
Table 1 -
Patient Characteristics by Very High-Risk–Qualifying Characteristic
a
Patient Characteristics
|
Total N = 5,078,111 |
Fracture while on Osteoporosis Therapy N = 125,646 |
Multiple Fractures over the Observation Period N = 118,738 |
Recent Fracture within 12 mo N = 90,926 |
Fracture on Medication with Known Adverse Effects on Bone N = 256,032 |
High Risk of falls
b
or History of Falls Resulting in Injury N = 5,033,106 |
| Age, yr |
| Mean (SD) |
72.7 (7.07) |
73.7 (6.34) |
73.9 (6.63) |
72.8 (7.18) |
73.3 (6.74) |
72.7 (7.07) |
| ≥65, n (%) |
4,276,893 (84.2) |
110,803 (88.2) |
103,784 (87.4) |
76,141 (83.7) |
221,324 (86.4) |
4,241,209 (84.3) |
| ≥75, n (%) |
2,952,019 (58.1) |
80,372 (64.0) |
80,554 (67.8) |
54,051 (59.5) |
159,529 (62.3) |
2,931,035 (58.2) |
| Sex, n (%) |
| Female |
4,417,465 (87.0) |
114,190 (90.9) |
101,534 (85.5) |
77,300 (85.0) |
222,778 (87.0) |
4,378,386 (87.0) |
| Insurance, n (%) |
| Commercial |
906,527 (17.9) |
21,039 (16.7) |
16,304 (13.7) |
16,209 (17.8) |
38,660 (15.1) |
896,207 (17.8) |
| Medicare |
1,901,462 (37.4) |
58,820 (46.8) |
41,802 (35.2) |
38,791 (42.7) |
118,869 (46.4) |
1,882,921 (37.4) |
| Other |
418,465 (8.2) |
10,441 (8.3) |
8,886 (7.5) |
9,114 (10.0) |
20,379 (8.0) |
414,539 (8.2) |
| Unknown |
1,851,657 (36.5) |
35,346 (28.1) |
51,746 (43.6) |
26,812 (29.5) |
78,124 (30.5) |
1,839,439 (36.6) |
| AACE/ACE qualifiers for very high fracture risk, n (%) |
| Fracture while on osteoporosis therapy |
125,646 (2.5) |
125,646 (100) |
20,298 (17.1) |
10,006 (11.0) |
43,641 (17.1) |
111,469 (2.2) |
| Multiple fractures over the observation period |
118,738 (2.3) |
20,298 (16.2) |
118,738 (100) |
24,517 (27.0) |
36,273 (14.2) |
112,152 (2.2) |
| Recent fracture within 12 mo |
90,926 (1.8) |
10,006 (8.0) |
24,517 (20.7) |
90,926 (100) |
19,999 (7.8) |
81,510 (1.6) |
| Fracture on medication with known adverse effects on bone |
256,032 (5.0) |
43,641 (34.7) |
36,273 (30.5) |
19,999 (22.0) |
256,032 (100) |
232,499 (4.6) |
| Patients at high risk of falls
a
or with a history of falls resulting in injury |
5,033,106 (99.1) |
111,469 (88.7) |
112,152 (94.5) |
81,510 (89.6) |
232,499 (90.8) |
5,033,106 (100) |
| History of taking glucocorticoids, n (%) |
1,885,529 (37.1) |
58,694 (46.7) |
48,416 (40.8) |
35,301 (38.8) |
159,224 (62.2) |
1,863,522 (37.0) |
| Hip fracture history, n (%) |
238,551 (4.7) |
22,893 (18.2) |
38,606 (32.5) |
20,207 (22.2) |
45,679 (17.8) |
233,656 (4.6) |
| Multiple vertebral fracture history, n (%) |
80,039 (1.6) |
17,479 (13.9) |
40,922 (34.5) |
7,827 (8.6) |
29,487 (11.5) |
75,384 (1.5) |
| Increased fall risks, n (%) |
| Neurological disorders |
| Parkinson disease |
160,833 (3.2) |
4,698 (3.7) |
5,658 (4.8) |
3,107 (3.4) |
9,256 (3.6) |
160,833 (3.2) |
| Seizure disorder |
351,634 (6.9) |
8,967 (7.1) |
10,983 (9.3) |
5,874 (6.5) |
25,368 (9.9) |
351,634 (7.0) |
| Peripheral neuropathy |
19,736 (0.4) |
380 (0.3) |
533 (0.5) |
407 (0.5) |
1,170 (0.5) |
19,736 (0.4) |
| Prior stroke |
736,720 (14.5) |
18,144 (14.4) |
21,747 (18.3) |
13,105 (14.4) |
43,584 (17.0) |
736,720 (14.6) |
| Dementia |
1,272,818 (25.1) |
33,374 (26.6) |
44,241 (37.3) |
24,616 (27.1) |
70,517 (27.5) |
1,272,818 (25.3) |
| Impaired gait or balance |
795,544 (15.7) |
25,508 (20.3) |
33,299 (28.0) |
10,331 (11.4) |
57,606 (22.5) |
795,544 (15.8) |
| Other fall risks |
| Autonomic dysfunction/orthostatic hypotension |
1,266,647 (24.9) |
33,806 (26.9) |
39,414 (33.2) |
25,552 (28.1) |
81,066 (31.7) |
1,266,647 (25.2) |
| Impaired vision |
845,933 (16.7) |
18,520 (14.7) |
18,628 (15.7) |
12,227 (13.5) |
40,915 (16.0) |
845,933 (16.8) |
| Impaired hearing |
938,167 (18.5) |
19,439 (15.5) |
19,615 (16.5) |
13,940 (15.3) |
40,329 (15.8) |
938,167 (18.6) |
| Frailty and deconditioning |
1,289,515 (25.4) |
40,528 (32.3) |
50,005 (42.1) |
32,310 (35.5) |
93,176 (36.4) |
1,289,515 (25.6) |
| Proximal myopathy |
9,373 (0.2) |
308 (0.3) |
313 (0.3) |
267 (0.3) |
748 (0.3) |
9,373 (0.2) |
| Sarcopenia |
107,529 (2.1) |
3,690 (2.9) |
5,187 (4.4) |
2,248 (2.5) |
8,689 (3.4) |
107,529 (2.1) |
AACE = American Association of Clinical Endocrinology; ACE = American College of Endocrinology.
aQualifying characteristics are not mutually exclusive. Patients may be included in more than one category.
bIncreased fall risks include neurological disorders (ie, Parkinson disease, seizure disorder, peripheral neuropathy, prior stroke, dementia, or impaired gait or balance) and other fall risks such as autonomic dysfunction/orthostatic hypotension, impaired vision, impaired hearing, frailty and deconditioning, proximal myopathy, or sarcopenia.
Most patients (5,033,106 [99.1%]) qualified as very high risk of fracture owing to a high risk of falls and/or because they had a history of falls resulting in injury (Table 1). Conditions associated with an increased risk of falls included neurological disorders (dementia [25.1%], impaired gait or balance [15.7%], history of stroke [14.5%], seizure disorder [6.9%], Parkinson disease [3.2%], or peripheral neuropathy [0.4%]) and/or other impairments of balance, reduced mobility, or functional deficits (frailty and deconditioning [25.4%], autonomic dysfunction/orthostatic hypotension [24.9%], impaired hearing [18.5%], impaired vision [16.7%], sarcopenia [2.1%], or proximal myopathy [0.2%]) (Table 1). A smaller number of patients were considered to be at very high risk of fracture based on other qualifiers (fracture while on medication with known adverse effects on bone, 256,032 [5.0%]; fracture while on a medication for osteoporosis, 125,646 [2.5%]; multiple fractures over the observation period, 118,738 [2.3%]; or fracture in the past 12 months, 90,926 [1.8%]). Of the patients with multiple fractures, 40,922 (34.5%) had multiple vertebral fractures. Among patients with a fracture in the past 12 months, 20,207 (22.2%) had sustained a hip fracture.
Treatment Patterns
Among patients considered to be at very high risk of fracture, 1,667,794 (32.8%) met the guideline-recommended criteria and did not have a contraindication or condition that would limit the use of any of the indicated osteoporosis medications. Of the 3,410,317 patients who were not eligible for osteoporosis therapy, 2,585,001 (75.8%) were excluded because of an upper gastrointestinal disorder (a contraindication for oral bisphosphonates). Other reasons patients were not eligible for osteoporosis therapy were malignancy (31.1%), acute renal failure (19.1%), and chronic renal failure (15.2%). A smaller number of patients were not eligible because of the presence of comorbidities including Paget disease, hypercalcemia, hyperparathyroidism, hypocalcemia, acute pancreatitis, osteosarcoma, or a history of myocardial infarction or stroke in the past year.
Of patients eligible for therapy (N = 1,667,794), only 280,777 (16.8%) received any osteoporosis treatment after being designated as very high risk during the identification period (Table 2). Among those who received treatment, alendronate, an alternative recommended therapy, was prescribed most often (178,629 [63.6%]) and 59,636 patients (21.2%) received guideline-recommended initial therapy (teriparatide, zoledronic acid, denosumab, abaloparatide, or romosozumab).
Table 2 -
Treatment Rate by Very High-Risk–Qualifying Characteristic, Sex, and Upper GI Disorder Status
| High-Risk–Qualifying Characteristic |
Excluding Patients with Upper GI Disorders |
Including Patients with Upper GI Disorders |
| Total, N = 5,078,111 |
| High risk eligible for treatment, n (%) |
1,667,794 (32.8) |
3,045,932 (60.0) |
| Treated |
280,777 (16.8) |
513,344 (16.9) |
| Untreated |
1,387,017 (83.2) |
2,532,588 (83.2) |
| Fracture while on osteoporosis medication, N = 125,646 |
| High risk eligible for treatment, n (%) |
36,120 (28.8) |
68,324 (54.4) |
| Treated |
17,906 (41.0) |
33,316 (48.8) |
| Untreated |
18,214 (50.4) |
35,008 (51.2) |
| Multiple fractures over the observation period, N = 118,738 |
| High risk eligible for treatment, n (%) |
24,730 (20.8) |
55,841 (47.0) |
| Treated |
5,031 (20.3) |
11,230 (20.1) |
| Untreated |
19,699 (79.7) |
44,611 (79.9) |
| Recent fracture, N = 90,926 |
| High risk eligible for treatment, n (%) |
28,360 (31.2) |
51,225 (56.3) |
| Treated |
7,582 (26.7) |
13,901 (27.1) |
| Untreated |
20,788 (73.3) |
37,324 (72.9) |
| Fracture on medication with known adverse effects on bone, N = 256,032 |
| High risk eligible for treatment, n (%) |
31,953 (12.5) |
117,076 (45.7) |
| Treated |
7,497 (23.5) |
27,484 (23.5) |
| Untreated |
24,456 (76.5) |
89,592 (76.5) |
| High risk of falls or history of falls resulting in injury, N = 5,033,106 |
| High risk eligible for treatment, n (%) |
1,650,313 (32.8) |
3,016,291 (59.9) |
| Treated |
275,023 (16.7) |
504,018 (16.7) |
| Untreated |
1,375,290 (83.3) |
2,512,273 (83.3) |
| Women, N = 4,417,465 |
| High risk eligible for treatment, n (%) |
1,448,770 (32.8) |
2,729,830 (61.8) |
| Treated |
263,767 (18.2) |
483,317 (17.7) |
| Untreated |
1,185,003 (81.8) |
2,246,513 (82.3) |
| Men, N = 660,593 |
| High risk eligible for treatment, n (%) |
178,988 (27.1) |
316,057 (47.8) |
| Treated |
17,010 (9.5) |
30,027 (9.5) |
| Untreated |
161,978 (90.5) |
286,030 (90.5) |
Within the subcategories for those at very high risk of fracture, the percentage of patients who were eligible for and received pharmacological therapies was highest for those who qualified as high risk because they sustained a fracture while on any medication for osteoporosis (41.0%) and lowest for patients at high risk or with a history of falls resulting in injury (16.7%) (Table 2 and Figure 3). In the remaining very high-risk categories, 26.7% of patients with a recent fracture, 23.5% of patients on medications with known adverse effects on bone, and 20.3% of patients with a history of multiple fractures were treated. Regardless of the very high-risk category, alendronate was the most common treatment, and only a small proportion of patients in each category was treated with a medication recommended as initial therapy for very high-risk patients (Figure 3).
Figure 3: Proportion of eligible patients who received treatment and treatment by a very high-risk–qualifying characteristic. OP = osteoporosis.
In a separate analysis by sex, the proportion treated was lower for men (17,010 [9.5%]) than women (263,767 [18.2%]) (Table 2). Among those who received treatment, similar proportions of women and men received initial therapy per recommended guidelines (women, 55,967 [21.2%]; men: 3,669 [21.6%]). Alendronate was prescribed most often for both women (166,259 [63.0%]) and men (12,370 [72.7%]).
When patients with gastrointestinal disorders were included in the analysis (Table 2), the treatment rate remained low for both men and women (513,344 [16.9%]). A total of 120,109 patients (23.4%) were initially treated per recommended guidelines while alendronate remained the most prevalent medication (315,808 [61.5%]). The treatment rate when women with gastrointestinal disorders (483,317 [17.7%]) were included was similar to when these women were excluded (263,767 [18.2%]). The treatment rate for men also did not change when men with gastrointestinal disorders were included in the analysis (9.5%).
Discussion
Based on the AACE/ACE guidelines, a large proportion of patients in this observational study met the criteria for very high risk of fracture. However, most were not treated for osteoporosis. At the time of this study, AACE guidelines from 2016, which recommended teriparatide, denosumab, or zoledronic acid as initial therapy for patients at especially high risk of fracture, were in use.24 However, most of those treated received alendronate. These guidelines were updated in 2020 to include abaloparatide and romosozumab, and at that time, clearer criteria for defining very high fracture risk, which could be used as an algorithm to identify patients in this study, were also adopted.14
Within each of the subcategories for those at very high risk of fracture, treatment patterns were comparable with the overall population (Table 1). Few patients were treated, and even smaller percentages received a medication recommended as initial therapy. Similarly, the current analyses by sex showed that most men and women at very high risk of fracture are untreated, with the rate of treatment being lower in men compared with women. For men, the associated risks and consequences of osteoporosis are less appreciated, perhaps in part because current treatment guidelines are mostly focused on women.16,25 Men tend to sustain fractures later in life, when they are also likely to have more comorbidities and a more compromised health status, resulting in a more rapid functional decline and increased mortality after a fracture.13,16 Furthermore, the risk of subsequent fractures after any sentinel fracture at any anatomical site is greater in men, even after adjusting for comorbidities,10 suggesting that other factors, possibly including bone quality/material properties, may play a role in outcomes for men. These findings reinforce the need for timely treatment to decrease the imminent and high risk of subsequent fractures in men.10,26
All validated risk assessment tools and widely accepted clinical practice guidelines recommend that patients should be evaluated for treatment of osteoporosis after a fragility fracture.14–16,24 Notwithstanding these recommendations, these results support previously reported findings that the osteoporosis treatment rate remains low after osteoporotic fracture.13,21 Even among patients with multiple fractures over the observation period, approximately one in five were treated with any osteoporosis medication. In our study, we found that most patients with osteoporosis were categorized as very high fracture risk based on more than one qualifier from the 2020 AACE guidelines and would have also been considered to be at higher risk according to the 2016 guidelines. However, these patients still did not receive treatment. Preexisting gastrointestinal disorders were also examined in this analysis. Approximately 60% of patients with gastrointestinal disorders were eligible for treatment, but the treatment rate was low. These findings suggest that many patients may be excluded from treatment out of caution for gastrointestinal side effects that are a concern with oral bisphosphonates and for whom anabolic agents are viable (and recommended) options.27–32 For patients at high risk of fracture, the benefit of treatment is great and the potential for serious adverse events and upper gastrointestinal events is low.16
Strong evidence supports the effectiveness of sequential therapy beginning with an anabolic agent, followed by antiresorptives toward rapidly reducing the risk of fracture compared with monotherapy.15,33 Furthermore, reduced treatment response to anabolic therapies has been reported after initial treatment with antiresorptives, followed by an anabolic agent.33–35 Thus, it is concerning that these results suggest that the practiced standard of care during the study period was mostly oral antiresorptives for this very high-risk group of patients. Although abaloparatide was not yet approved for use in 2016, teriparatide, denosumab, or zoledronic acid was recommended for patients who were at very high fracture risk at the time of this study.
Limitations of this evaluation were that available administrative claims data did not include race and socioeconomic status (which may be associated with disparities in the management of osteoporosis);36 all available osteoporosis medications (eg, estrogen), and data for some risk factors were missing (ie, T-score from dual‐energy x‐ray absorptiometry [DXA] scans, family history of osteoporotic fractures, and lifestyle factors such as smoking). Many risk factors in this analysis can be used without necessitating DXA results. The high incidence of subsequent fracture after an initial fragility fracture should be sufficient to warrant treatment.7,37 In addition, data were from 2018, and the most recent guidelines outlining risk-based factors for patients at very high risk of fracture were issued in 2020.14 However, evidence was emerging in the literature before 2020 supporting the initial treatment of these patients with anabolic therapy.15,33,38,39
Undertreatment (ie, lack of treatment initiation and risk-based treatment) is a serious concern for patients with osteoporosis who are at very high risk of fracture. Factors associated with very high risk of fracture are described in clinical practice guidelines, which facilitate identification of these patients without the requirement for DXA. Patients have the potential to have better outcomes when osteoporosis treatment decisions are based on risk-based assessment and evidence-based clinical practice guidelines.
References
1. Miller PD: Underdiagnoses and undertreatment of osteoporosis: The battle to be won. J Clin Endocrinol Metab 2016;101:852-859.
2. Morris CA, Cabral D, Cheng H, et al.: Patterns of bone mineral density testing: Current guidelines, testing rates, and interventions. J Gen Intern Med 2004;19:783-790.
3. Bliuc D, Alarkawi D, Nguyen TV, Eisman JA, Center JR: Risk of subsequent fractures and mortality in elderly women and men with fragility fractures with and without osteoporotic bone density: The dubbo osteoporosis epidemiology study. J Bone Miner Res 2015;30:637-646.
4. Gold DT, Williams SA, Weiss RJ, et al.: Impact of fractures on quality of life in patients with osteoporosis: A US cross-sectional survey. J Drug Assess 2019;8:175-183.
5. Office of the Surgeon General (US): Bone Health and Osteoporosis: A Report of the Surgeon General. Reports of the Surgeon General. Rockville (MD), Office of the Surgeon General, 2004.
6. Singer A, Exuzides A, Spangler L, et al.: Burden of illness for osteoporotic fractures compared with other serious diseases among postmenopausal women in the United States. Mayo Clinic Proc 2015;90:53-62.
7. Balasubramanian A, Zhang J, Chen L, et al.: Risk of subsequent fracture after prior fracture among older women. Osteoporos Int 2019;30:79-92.
8. Johansson H, Siggeirsdóttir K, Harvey NC, et al.: Imminent risk of fracture after fracture. Osteoporos Int 2017;28:775-780.
9. Kanis JA, Johnell O, De Laet C, et al.: A meta-analysis of previous fracture and subsequent fracture risk. Bone 2004;35:375-382.
10. Morin SN, Yan L, Lix LM, Leslie WD: Long-term risk of subsequent major osteoporotic fracture and hip fracture in men and women: A population-based observational study with a 25-year follow-up. Osteoporos Int 2021;32:2525-2532.
11. Balasubramanian A, Tosi LL, Lane JM, Dirschl DR, Ho P-R, O'Malley CD: Declining rates of osteoporosis management following fragility fractures in the U.S., 2000 through 2009. J Bone Joint Surg 2014;96:e52.
12. Williams SA, Chastek B, Sundquist K, et al.: Economic burden of osteoporotic fractures in US managed care enrollees. Am J Manag Care 2020;26:e142-e149.
13. Williams SA, Daigle SG, Weiss R, Wang Y, Arora T, Curtis JR: Economic burden of osteoporosis-related fractures in the US Medicare population. Ann Pharmacother 2021;55:821-829.
14. Camacho PM, Petak SM, Binkley N, et al.: American association of clinical endocrinologists/American college of endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis-2020 update executive summary. Endocr Pract 2020;26:564-570.
15. Cosman F: Anabolic and antiresorptive therapy for osteoporosis: Combination and sequential approaches. Curr Osteoporos Rep 2014;12:385-395.
16. US Preventive Services Task Force, Curry SJ, Krist AH, et al.: Screening for osteoporosis to prevent fractures: US preventive services task force recommendation statement. JAMA 2018;319:2521-2531.
17. Cosman F, Crittenden DB, Adachi JD, et al.: Romosozumab treatment in postmenopausal women with osteoporosis. New Engl J Med 2016;375:1532-1543.
18. McCloskey EV, Johansson H, Harvey NC, Lorentzon M, Shi Y, Kanis JA: Romosozumab efficacy on fracture outcomes is greater in patients at high baseline fracture risk: A post hoc analysis of the first year of the frame study. Osteoporos Int 2021;32:1601-1608.
19. Miller PD, Hattersley G, Riis BJ, et al.: Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis: A randomized clinical trial. JAMA 2016;316:722-733.
20. Nakamura T, Sugimoto T, Nakano T, et al.: Randomized Teriparatide [human parathyroid hormone (PTH) 1-34] Once-Weekly Efficacy Research (TOWER) trial for examining the reduction in new vertebral fractures in subjects with primary osteoporosis and high fracture risk. J Clin Endocrinol Metab 2012;97:3097-3106.
21. HEDIS: Osteoporosis Testing and Management in Women who had a Fracture. Available from:
https://www.ncqa.org/hedis/measures/osteoporosis-management-in-women-who-had-a-fracture-omw/. Accessed January 19, 2022.
22. Wright NC, Daigle SG, Melton ME, Delzell ES, Balasubramanian A, Curtis JR: The design and validation of a new algorithm to identify incident fractures in administrative claims data. J Bone Miner Res 2019;34:1798-1807.
23. Papapetrou PD: Bisphosphonate-associated adverse events. Hormones (Athens) 2009;8:96-110.
24. Camacho PM, Petak SM, Binkley N, et al: American association of clinical endocrinologists/American college of endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis ‐ 2016. Endocr Pract 2016;26:1-42.
25. Meryn S: Undertreatment of osteoporosis in men. Arch Intern Med 2005;165:241.
26. Center JR, Bliuc D, Nguyen TV, Eisman JA: Risk of subsequent fracture after low-trauma fracture in men and women. JAMA 2007;297:387-394.
27. TYMLOS. Prescribing information. US food and drug administration; 2017.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208743lbl.pdf Accessed January 19, 2022.
28. Fosamax. Prescribing information. US food and drug administration. 2012.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021575s017lbl.pdf Accessed January 19, 2022.
29. Prolia. Prescribing information. US food and drug administration; 2010.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/125320s0000lbl.pdf Accessed January 19, 2022.
30. Forteo. Prescribing information. US food and drug administration; 2020.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021318s053lbl.pdf Accessed January 19, 2022.
31. Evenity. Prescribing information. US food and drug administration; 2019.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761062s000lbl.pdf Accessed January 19, 2022.
32. Reyes C, Hitz M, Prieto-Alhambra D, Abrahamsen B: Risks and benefits of bisphosphonate therapies. J Cel Biochem 2016;117:20-28.
33. Cosman F, Nieves JW, Dempster DW: Treatment sequence matters: Anabolic and antiresorptive therapy for osteoporosis. J Bone Miner Res 2017;32:198-202.
34. Boonen S, Marin F, Obermayer-Pietsch B, et al.: Effects of previous antiresorptive therapy on the bone mineral density response to two years of teriparatide treatment in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2008;93:852-860.
35. Ettinger B, Martin SJ, Crans G, Pavo I: Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J Bone Miner Res 2004;19:745-751.
36. Noel SE, Santos MP, Wright NC: Racial and ethnic disparities in bone health and outcomes in the United States. J Bone Miner Res 2021;36:1881-1905.
37. Shuhart CR, Yeap SS, Anderson PA, et al.: Executive summary of the 2019 ISCD position development conference on monitoring treatment, DXA cross-calibration and least significant change, spinal cord injury, peri-prosthetic and orthopedic bone health, transgender medicine, and pediatrics. J Clin Densitom 2019;22:453-471.
38. Black DM, Bilezikian JP, Ensrud KE, et al.: One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med 2005;353:555-565.
39. Rittmaster RS, Bolognese M, Ettinger MP, et al.: Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab 2000;85:2129-2134.
