Bone turnover markers reference database in five Southeast Asian countries.

Osteoporosis is highly prevalent, particularly in developing countries. However, bone turnover marker reference ranges for management of osteoporosis in Asian population are yet to be explored and established. Thus, this study aims to develop a regional bone turnover markers (BTMs) reference database by combining country-specific reference database from five ASEAN countries: Malaysia, the Philippines, Singapore, Thailand, and Vietnam. We established a healthy reference population of 746 healthy premenopausal women aged 20 to 44 years old. Serum Procollagen 1 N-Terminal Propeptide (P1NP), Osteocalcin (OC), and Beta-Crosslaps (CTX) concentrations were measured using an automated immunoassay analyzer system, the cobas® modular analyzer systems (Roche Diagnostic Gmbh). The reference interval was defined as the central 95 % range. The estimated reference interval for CTX was 128 to 811 ng/L, OC was 9.0 to 33.0 µg/L, and for P1NP, the range was 22.8 to 96.5 µg/L. Comparison across countries showed that Singaporeans had the highest levels of median CTX along with Thais and Filipinos, who had significantly higher levels of P1NP and OC. Exploratory analysis on the associations with age showed that BTMs decreased with increasing age at 20 to 29 years old and plateaued after 30 years old. When excluding participants in their 20s, the reference interval estimated were CTX: 117-678 ng/L, P1NP: 21.6-85.8 µg/L and OC: 3.5-27.0 µg/L respectively. To the best of our knowledge, this is the first study to report BTMs reference intervals based on a healthy premenopausal Southeast Asian population which will contribute to the appropriate assessment and monitoring of bone turnover rate in the evaluation and management of osteoporosis in the Southeast Asian region. LAY SUMMARY: Osteoporosis is a common health issue, especially in developing countries. However, there is a lack of information on bone health markers specific to the Southeast Asian population. This study aimed to fill this gap by creating a reference database for bone turnover markers (BTMs) in Southeast Asian countries, including Malaysia, the Philippines, Singapore, Thailand, and Vietnam. The researchers studied 746 healthy women aged 20 to 44 years and measured blood markers related to bone health. The reference interval, representing the normal range, was determined. For example, the normal range for CTX was found to be 128 to 811 ng/L, for Osteocalcin was 9.0 to 33.0 µg/L, and for P1NP, the range was 22.8 to 96.5 µg/L. When excluding participants in their 20s, the reference intervals estimated were CTX: 117-678 ng/L, P1NP: 21.6-85.8 µg/L and OC: 3.5-27.0 µg/L respectively. Comparing the results across countries, Singaporeans, Thais, and Filipinos showed variations in their biochemical bone marker levels. Additionally, the study observed changes in the levels with age, with a decrease in BTMs observed after the age of 30. This groundbreaking study provides the first-ever reference intervals for BTMs in a healthy premenopausal Southeast Asian population. These findings will help in the proper assessment and monitoring of bone health, contributing to the management of osteoporosis in the Southeast Asian region.

Service availability and readiness for hip fracture care in low- and middle-income countries in South and Southeast Asia.

Aims: The aim of this study was to describe the current pathways of care for patients with a fracture of the hip in five low- and middle-income countries (LMIC) in South Asia (Nepal and Sri Lanka) and Southeast Asia (Malaysia, Thailand, and the Philippines). Methods: The World Health Organization Service Availability and Readiness Assessment tool was used to collect data on the care of hip fractures in Malaysia, Thailand, the Philippines, Sri Lanka, and Nepal. Respondents were asked to provide details about the current pathway of care for patients with hip fracture, including pre-hospital transport, time to admission, time to surgery, and time to weightbearing, along with healthcare professionals involved at different stages of care, information on discharge, and patient follow-up. Results: Responses were received from 98 representative hospitals across the five countries. Most hospitals were publicly funded. There was consistency in clinical pathways of care within country, but considerable variation between countries. Patients mostly travel to hospital via ambulance (both publicly- and privately-funded) or private transport, with only half arriving at hospital within 12 hours of their injury. Access to surgery was variable and time to surgery ranged between one day and more than five days. The majority of hospitals mobilized patients on the first or second day after surgery, but there was notable variation in postoperative weightbearing protocols. Senior medical input was variable and specialist orthogeriatric expertise was unavailable in most hospitals. Conclusion: This study provides the first step in mapping care pathways for patients with hip fracture in LMIC in South Asia. The previous lack of data in these countries hampers efforts to identify quality standards (key performance indicators) that are relevant to each different healthcare system.

Summary of the Thai Osteoporosis Foundation (TOPF) Clinical Practice Guideline on the diagnosis and management of osteoporosis 2021.

Objectives: The Thai Osteoporosis Foundation (TOPF) is an academic organization that consists of a multidisciplinary group of healthcare professionals managing osteoporosis. The first clinical practice guideline for diagnosing and managing osteoporosis in Thailand was published by the TOPF in 2010, then updated in 2016 and 2021. This paper presents important updates of the guideline for the diagnosis and management of osteoporosis in Thailand. Methods: A panel of experts in the field of osteoporosis was recruited by the TOPF to review and update the TOPF position statement from 2016. Evidence was searched using the MEDLINE database through PubMed. Primary writers submitted their first drafts, which were reviewed, discussed, and integrated into the final document. Recommendations are based on reviews of the clinical evidence and experts' opinions. The recommendations are classified using the Grading of Recommendations, Assessment, Development, and Evaluation classification system. Results: The updated guideline comprises 90 recommendations divided into 12 main topics. This paper summarizes the recommendations focused on 4 main topics: the diagnosis and evaluation of osteoporosis, fracture risk assessment and indications for bone mineral density measurement, fracture risk categorization, management according to fracture risk, and pharmacological management of osteoporosis. Conclusions: This updated clinical practice guideline is a practical tool to assist healthcare professionals in diagnosing, evaluating, and managing osteoporosis in Thailand.

Mortality and outcome in fragility hip fracture care during COVID-19 pandemic in Police General Hospital, Thailand.

Objectives: The objective of this study is to assess outcomes and patient's mortality of Police General Hospital's fracture liaison service (PGH's FLS) during Coronavirus disease 2019 (COVID-19) outbreak comparing to the former period. Methods: Retrospective cohort study was performed in patients aged 50 or older who were admitted with fragility hip fracture in Police General Hospital, Bangkok, between January 1, 2018 to December 31, 2019 (before pandemic) comparing to January 1, 2020 to December 31, 2021 (pandemic) using the electronic database. The outcomes were mortality and other outcomes in one-year follow up. Results: A total of 139 fragility hip fractures were recorded in 2018-2019 (before pandemic) compared with 125 in 2020-2021 (pandemic). The 30-day mortality in hip fracture numerically increased from 0% to 2.4% during the pandemic. One-year mortality was significantly escalated from 2 cases (1.4%) to 5 cases (4%) (P = 0.033). However, the cause of mortality was not related with COVID-19 infection. We also found a significantly shorter time to surgery but longer wait time for bone mineral density (BMD) testing and initiation of osteoporosis medication in pandemic period. Conclusions: The results of this study in COVID-19 pandemic period, 1-year mortality rate was significantly higher but they were not related with COVID-19 infection. We also found longer time to initial BMD testing and anti-osteoporotic medication and more loss of follow up, causing lower anti-osteoporotic medication taking. In contrast, the time to surgery became shorter during the pandemic.

Trabecular bone score as an additional therapeutic decision tool in osteoporosis and osteopenia.

Objectives: To evaluate the role of trabecular bone score (TBS), in addition to bone mineral density (BMD), and to aid decision making to initiate anti-osteoporotic treatment in postmenopausal women with osteopenia. Methods: TBS was assessed in a cohort of Thai postmenopausal women with BMD of femoral neck (FN), total hip (TH), and lumbar spine (LS) performed at the Police General Hospital, Bangkok, Thailand from July 2019 to October 2020. We retrospectively reviewed hospital database for underlying diseases, medication, and fractures, including relevant imaging and vertebral fracture assessment (VFA). Patients with previous osteoporosis treatment, skeletal malignancy, high-energy trauma, and uninterpretable BMD were excluded. Results: In total there were 407 postmenopausal women, including 115 with osteoporotic fractures. The mean TBS of the cohort was 1.264 ± 0.005. The proportion of osteoporotic subjects ranged from 9.1% by TH BMD to 27.0% by lowest BMD. In fractured patients, 21.7%-54.8% were found to have osteoporosis while osteopenia was found in 37.4%-43.5%. Among subjects with osteopenia and degraded TBS, fractures ranged from 21.7 to 50.9%. Addition of osteopenic subjects with degraded microarchitecture yielded a significantly higher number of subjects eligible for treatment with 3.25-fold increase in non-fractured participants, and 7 to 11 additional osteopenic patients should be treated to detect 1 fracture. Conclusions: Addition of TBS helped capturing osteopenic women with high risk of fracture. Decision to treat osteopenic women with degraded TBS increased the number of patients receiving treatment. We recommend evaluating TBS in osteopenic women without fractures to aid therapeutic decision on treatment initiation.

Trabecular Bone Score as a Risk Factor of Major Osteoporotic Fracture in Postmenopausal Women: The First Study in Thailand.

OBJECTIVES: To compare the trabecular bone score (TBS) between Thai postmenopausal women with and without major osteoporotic fracture, and to determine whether TBS is associated with fracture risk. METHODS: All postmenopausal women sent for dual-energy X-ray absorptiometry (DXA) at the Police General Hospital were retrospectively recruited. The hospital's online database and radiographs were reviewed to collect information on underlying disease, medication, previous fractures, bone mineral density, and trabecular bone score. Patients with anti-osteoporotic medication use, skeletal malignancy, fracture from high-energy trauma, and uninterpretable DXA images were excluded. RESULTS: A total of 407 Thai postmenopausal women were enrolled. They were divided into 292 women without fractures and 115 women with major osteoporotic fractures. The fracture group was older (73.36 ± 9.95 vs. 66.00 ± 8.58, P < 0.001) and had lower serum 25-hydroxyvitamin D levels (23.28 ± 9.09 vs. 26.44 ± 9.20, P = 0.023). The mean TBS was lower in the fracture group, compared to the non-fracture group (1.244 ± 0.101 vs. 1.272 ± 0.099, P = 0.011). The subgroup analysis resulted in noticeably lower TBS in spine fracture, but not other fracture sites. The odds ratio of fracture was 1.355 (P = 0.013) for a decrease in one standard deviation of TBS. CONCLUSIONS: TBS was significantly lower in postmenopausal women having fractures with an odd ratio of 1.355 (P = 0.013) per SD decrease in TBS. Categorizing by fracture sites, TBS was only found to be noticeably lower in the lumbar spine despite similar lumbar spine bone mineral density.

Efficacy of plain cholecalciferol versus ergocalciferol in raising serum vitamin D level in Thai female healthcare workers.

Objectives: To compare the efficacy of cholecalciferol and ergocalciferol in raising 25-hydroxyvitamin D (25(OH)D) level in Thai female healthcare workers. Methods: A randomized control trial was conducted in healthy female healthcare workers. Randomization allocated the participants into vitamin D2 group (N = 43), receiving ergocalciferol 20,000 IU weekly and vitamin D3 group (N = 40), receiving cholecalciferol 1000 IU daily for 12 months. Venous blood sample was collected at baseline, 6 and 12 months for serum 25(OH)D, parathyroid hormone and calcium. Compliance was also assessed. Results: The mean age of the participants was 50.6 ± 9.9 and 50.9 ± 8.4 years in vitamin D2 and D3 groups (P = 0.884). The mean 25(OH)D levels were 16.91 ± 6.07 ng/mL and 17.62 ± 4.39 ng/mL (P = 0.547), respectively. Both groups had significant improvement in 25(OH)D level at 6 months (from 16.91 ± 6.07 to 21.67 ± 5.11 ng/mL and 17.62 ± 4.39 to 26.03 ± 6.59 ng/mL in vitamin D2 and D3 group). Improvement was significantly greater with cholecalciferol (P = 0.018). The level plateaued afterwards in both groups. Only cholecalciferol could increase 25(OH)D in participants without vitamin D deficiency (6.88 ± 4.20 ng/mL increment). Compliance was significantly better in vitamin D2 group (P = 0.025). Conclusions: Daily cholecalciferol supplementation resulted in a larger increase in serum 25(OH)D level during the first 6 months comparing to weekly ergocalciferol. While vitamin D3 could increase serum 25(OH)D level in all participants, vitamin D2 could not do so in participants without vitamin D deficiency.

Comparison of bone mineral density and vertebral fracture assessment in postmenopausal women with and without distal radius fractures.

OBJECTIVES: To compare bone mineral density (BMD) in Thai postmenopausal women with and without distal radius fracture, and to investigate the role of vertebral fracture assessment (VFA) in diagnosing osteoporosis after distal radius fracture. METHODS: A cross-sectional study was conducted in Thai postmenopausal women with and without distal radius fracture. BMDs of the femoral neck (FN), total hip (TH), lumbar spine (LS), and VFA were obtained within 2 weeks of injury. BMD were compared between groups. Participants were classified into osteoporosis, osteopenia or normal using BMD alone, and BMD plus VFA, where a mere presence of vertebral compression fracture indicated osteoporosis. RESULTS: Fifty postmenopausal women with distal radius fractures and 111 non-fracture postmenopausal women participated. The mean BMD was significantly lower at all sites in the fracture group (FN BMD 0.590 ± 0.075 vs 0.671 ± 0.090, p = 0.007; TH BMD 0.742 ± 0.103 vs 0.828 ± 0.116, P = 0.009; LS BMD 0.799 ± 0.107 vs 0.890 ± 0.111, P = 0.009 in the fracture vs non-fracture group respectively). VFA increased the prevalence of osteoporosis from 16 (32%) to 23 (46%) in the fracture group, and 7 (6.31%) to 17 (16.22%) in the non-fracture group, with a number needed to treat 9. CONCLUSIONS: Postmenopausal women with distal radius fractures had lower BMD. Incorporating VFA into diagnosis of osteoporosis increased the prevalence of osteoporosis in both fracture and non-fracture groups. Postmenopausal women aged 50 years or older with distal radius fracture are a good target for the investigation of osteoporosis.

The effectiveness of Police General Hospital's fracture liaison service (PGH's FLS) implementation after 5 years: A prospective cohort study.

OBJECTIVES: The purpose of the study is to assess the effectiveness of fracture liaison service (FLS) after 5-year implementation to close the secondary fracture care gap, ensuring that patients receive osteoporosis assessment, intervention, and treatment, therefore, reducing the fracture risk at Police General Hospital (PGH). METHODS: A prospective cohort study was conducted. We studied male and female, ≥ 50 years old who presented with a fragility hip fracture and participated in PGH's FLS from April 1, 2014-March 31, 2019 (5 years implementation). The sample size was 353 patients, with 1-year follow-up. The data were compared with a previous study, before the commencement of the FLS. RESULTS: After 1-year follow up, the mortality rates were 5.95% and there were only 8 patients who had secondary fractures (2.93%), which showed a decrease of 30% from before FLS implementation. Post-injury bone mineral density (BMD) rates were increased from 28.33% to 85.84%, osteoporosis treatment rates were increased from 40.8% to 89.38%, and the time to surgery and hospitalization decreased from 7.9 to 5.0 days, and 23.2 to 19.6 days, respectively, all with statistical significance (P < 0.001). However, the 1-year mortality rates were not significant when compared to the previous study. CONCLUSIONS: Patients with fragility hip fractures participating in FLS after 5-year implementation at PGH had significantly higher post-injury BMD and osteoporosis treatment rates and significantly shorter in time to surgery and hospitalization. This showed that secondary fracture rates were lower than before the project at 1-year of follow up.

Quality of life and factors that affect osteoporotic hip fracture patients in Thailand.

OBJECTIVES: The aim of this study was to report the health-related quality of life (HRQoL) over the first year after osteoporotic hip fracture and to identify the factors associated with HRQoL in Police General Hospital in Thailand. METHODS: A prospective cohort study was conducted. 139 subjects who had osteoporotic hip fracture were recruited, which they will be assessed during the preinjury recall and at 3, 6, and 12 months after the fracture. HRQoL was measured as Thailand health state utility values (THSUVs), which derived from EuroQol-5-Dimension-3-Level. Factors associated with the change in QoL were analyzed. RESULTS: One hundred thirty-six patients with a hip fracture were included for analysis. Their mean age was 82 ± 11 years old. The mean ± standard deviation (SD) of QoL score and EQ VAS at 12-month follow-up period were lower than before the fracture ([0.68 ± 0.105 vs. 0.55 ± 0.183] and [85 ± 10.5 vs. 79 ± 19.2]). The mean ± SD of QoL score and EQ VAS, compared before and after the fracture was estimated at -0.13 ± 0.164 and -6 ± 14.7 (P = 0.01). The positive influences on the change in QoL score were present in the subject, who are younger than 80 years old, had normal or high body mass index (BMI), and had operative treatment. CONCLUSIONS: Osteoporotic hip fractures incurred substantial loss in HRQoL which was markedly impaired at first 3 months after hip fracture and after that HRQoL was improved but did not return to prefracture levels. So primary prevention of fall is more important. The changes in HRQoL, was influenced by age, BMI, and operative treatment.

Comparative outcome of PFNA, Gamma nails, PCCP, Medoff plate, LISS and dynamic hip screws for fixation in elderly trochanteric fractures: a systematic review and network meta-analysis of randomized controlled trials.

The ideal implant for the treatment of an unstable intertrochanteric femoral fracture is still a matter of discussion. The aim of this systematic review is to conduct a network meta-analysis of randomized controlled trials (RCTs) comparing clinical outcomes between dynamic hip screws (DHS), Medoff sliding plating, percutaneous compression plating (PCCP), proximal femoral nails (PFN), Gamma nails and less invasive stabilization system fixation in femoral trochanteric fractures in the elderly. These clinical outcomes consist of total intra-operative time, intra-operative fluoroscopy time, intra-operative blood loss, blood component transfusion, length of hospital stay, postoperative general complications, wound complications, late complications and reoperation rates. This systematic review was conducted using PubMed and Scopus search engines for RCTs comparing clinical outcomes between treatments from inception to February 22, 2015. Thirty-six of 785 studies identified were eligible. Compared to the other implants, PCCP showed the lowest total operative time and units of blood transfusion with an unstandardized mean difference (UMD) of 29.27 min (95% CI 5.24, 53.50) and 0.89 units (95% CI 0.52, 1.25). The lowest incidence of general complications, wound complications and late complications of PCCP was 0.09 (95% CI 0.04, 0.18), 0.01 (95% CI 0.01, 0.04) and 0.05 (95% CI 0.02, 0.11), respectively, when compared to others. The lowest fluoroscopic time was with DHS with an UMD of 0.24 min (95% CI 0.16, 0.32), whereas the lowest blood loss and shortest hospital stay were with PFN with an UMD of 233.61 ml of blood loss (95% CI 153.17, 314.04) and 7.23 days of hospital stay (95% CI 7.15, 7.31) when compared to all other fixation methods. Reoperation rates of all implants had no statistically significant difference. The network meta-analysis suggested that fixation with PCCP significantly shortens operative time and decreases the units of blood transfusion required, while also lowering risks of general complications, wound complications and late complications when compared to fixation. Use of PFN showed the least intra-operative blood loss and shortest hospital stay. Multiple active treatment comparisons indicate that PCCP fixation in trochanteric fractures in the elderly is the treatment of choice in terms of intra-operative outcomes and postoperative complications.

Evaluation of Police General Hospital's Fracture Liaison Service (PGH's FLS): The first study of a Fracture Liaison Service in Thailand.

OBJECTIVES: The purpose of the study was to assess the effectiveness of the Fracture Liaison service (FLS) in preventing secondary fracture and decreasing 1-year mortality rate after osteoporotic hip fracture, in patients at Police General Hospital, Bangkok, Thailand. METHODS: A prospective cohort study was conducted. We studied male and female patients, 50 years of age and older, who presented with a fragility fracture around the hip due to low energy trauma and were admitted to Police General Hospital, participating in PGH's Liaison service from April 1, 2014-March 30, 2015. The sample size was 75 patients, with a follow up time of 1 year. The data from this study was compared with that of a previous study done by Tanawat A. et al. [9] prior to commencement of the FLS project. RESULTS: After a follow up period of 1 year, the mortality rate was measured to be 10.7% and there was no evidence of secondary fragility fracture. Post-injury bone mineral density follow up and osteoporotic medication treatment rates were 48% and 80%, respectively. Patients who participated in the project were found to have a decreasing rate of secondary fracture from 30% to 0% (P < 0.0001), an increasing post-injury BMD follow up rate from 28.3% to 48% (P = 0.0053), and an increase in post-injury osteoporotic medication administration rate from 40.8% to 80% (P = 0.0148), all with statistical significance. However, the 1-year mortality rate was not significant (P = 0.731) when compared to the previous study. CONCLUSIONS: Patients with recent hip fractures participating in the Fracture Liaison service had a significantly higher post-injury BMD follow up and osteoporotic medication administration rates. This resulted in a lower risk of secondary fracture than those who did not participate in the Fracture Liaison service at a follow up time of one year.

Arthroscopic anatomic glenoid reconstruction using an autologous iliac crest bone grafting technique.

BACKGROUND: Open bone block procedures for glenohumeral stabilization have been used for a long time. With the advancement of arthroscopic techniques and the development of sophisticated instruments and implants, the insertion of the bone block can be performed by an all-arthroscopic approach. The purpose of this study was to evaluate the clinical and radiologic results after an arthroscopic anatomic glenoid reconstruction using an all-arthroscopic, autologous tricortical iliac crest bone grafting technique. MATERIALS AND METHODS: Fifteen patients (1 female and 14 male patients; mean age, 31.4 years [range, 17-49 years]) underwent reconstruction of significant glenoid defects in cases of recurrent shoulder instability by the aforementioned technique. The patients were followed up clinically (range of motion, Constant score, Rowe score, Subjective Shoulder Value, and Western Ontario Shoulder Instability Index) and radiographically (with true anteroposterior and axillary views, as well as 2-/3-dimensional computed tomography [glenoid configuration, signs of graft resorption, bone consolidation, and glenoid index]). RESULTS: After a mean follow-up period of 20.6 months (range, 12-65 months), the Constant score averaged 85.0 points (range, 73-98 points; contralateral side, 89.6 points [range, 78-96 points]), the Rowe score averaged 88.0 points (range, 65-100 points), the Subjective Shoulder Value averaged 84.5% (range, 50%-100%), and the Western Ontario Shoulder Instability Index averaged 76.7% (range, 46%-93%). No recurrent subluxations or dislocations were observed. Radiographically, computed tomography imaging showed a consolidated autograft in all cases. The glenoid index increased from a mean of 0.77 preoperatively to 1.16 immediately postoperatively; at the time of last follow-up, the glenoid index decreased to 1.04. CONCLUSION: The arthroscopic reconstruction of anteroinferior glenoid defects re-creates the pear-shaped anatomy of the anteroinferior glenoid and leads to good to excellent early clinical results.

Total knee replacement following repeated cycles of intra-articular sodium hyaluronate (500-730 Kda) in failed conservative treatment of knee osteoarthritis: a 54-month follow-up.

BACKGROUND: Treatment with repeated cycles of Intra-Articular Sodium Hyaluronate (IA-HA), from previous study, can improve symptoms and delay surgical interventions in knee osteoarthritis patients who failed conservative treatment within minimum 2-years follow-up. This is a continued study to follow-up responded patients in the mentioned study whether continuing treatment with IA-HA could prolong time to surgery until the end of follow-up. OBJECTIVE: To evaluate the incidence of total knee replacement (TKR) in patients receiving repeated cycles of IA-HA during a 54-month follow-up period. MATERIAL AND METHOD: This was a prospective cohort study with 54-month follow-up period. All patients received at least a single course of 3-weekly injections of IA-HA (500-730 Kilodalton, Hyalgan). Patients who well responded to the treatment were recommended to repeat the administration of a 3-weekly injections every 6-12 months based on their symptoms. The incidence of TKR and time was recorded. Time to event analysis using Kaplan-Meier survival analysis was performed. RESULTS: 183 patients were recruited during March 2001 and March 2004 and followed-up until October 2008. Patients were classified into three groups according to Ahlback radiological grading system. 46 patients were in group 1 (Ahlback grade I-II), 70 patients were in group 2 (Ahlback grade III-IV) and 67 patients were in group 3 (Ahlback grade V). The incidence of TKR was 28.4% with a mean time to TKR of 15.4 months (0.7-51.7 months). For the rest of patients who had no TKR during study period (80.4%, 64.3% and 73.1% for group 1, 2, and 3 respectively), their mean follow-up time was 45.6 months (19.0-53.1 months). Mean survival time was 42.1 months (95% CI = 39.4-44.9 months). CONCLUSION: The repeated cycles of intra-articular sodium hyaluronate treatment in delay time to TKR in patients with knee osteoarthritis which failed conservative treatment was found efficacious during a 54-month follow-up period.