Secondary Causes Of Osteoporosis Research Articles

Bone metabolism disorders in endogenous Cushing syndrome

Endogenous Cushing syndrome (CS) leading to an overproduction of cortisol is a major cause of secondary osteoporosis. Bone complications in CS, despite the fact that they not only reduce the quality of life, but also increase mortality, are still underdiagnosed. Hypercortisolemia results, among others, in a reduced bone mineral density (BMD). However, an increased risk of fracture in CS may occur in bones with only a slight reduction or even normal BMD. The disease is usually insidious, prolonging the period of hypercortisolemia before diagnosis. Therefore, skeletal complications such as reduced BMD, osteoporosis and fractures are common in CS. Osteoporosis has a prevalence of 40-70%, osteopenia 80-85% and fractures 30-70% in patients with CS (1, 2). Fractures usually involve the lumbar and thoracic vertebrae, hips, ribs and pelvis as the trabecular bone is mainly affected. The most common pathogenesis of CS leading to bone lesions remains a topic of researches. Chronic hypercortisolemia leads not only to the reduction of BMD but also to changes in bone microarchitecture. Increased resorption and inhibited bone formation are the main mechanisms described in CS. Reversal of changes in bone mineral density after recovery from CS has been observed. Surgical treatment of pituitary or adrenal tumours should be the first line of treatment. However, vitamin D and calcium supplementation as well as treatment with antiresorptive drugs seems to be also essential. In this paper we presents a review of the current literature on bone complications in endogenous CS.

Risk of fracture in women with glucocorticoid requiring diseases is independent from glucocorticoid use: An analysis on a nation-wide database

ObjectiveGlucocorticoid-induced osteoporosis (GIOP) is a common cause of secondary osteoporosis. However, glucocorticoid requiring diseases pose a risk themselves for fracture. The aim of the present study was to determine the risk of fracture associated with variety of glucocorticoid requiring diseases independently from glucocorticoid use and other risk factors for osteoporosis. MethodsWe conducted a retrospective cross-sectional analysis of a nation-wide cohort (DeFRACalc79 database). We used multivariable regression analysis adjusting for several risk factors for fracture and glucocorticoid intake to estimate the independent role of glucocorticoid requiring illnesses on fracture risk. ResultsWe found that patients with rheumatoid arthritis, connective tissue diseases, chronic obstructive pulmonary disease (COPD) and neurological diseases were at greater risk of vertebral or hip fracture (crude ORs 1.31, 1.20, 1.92 and 2.97 respectively). After adjusting for potential confounders COPD and neurological diseases remained significantly associated with an increased risk of vertebral or hip fractures (aORs 1.33, 95 % CI 1.18–1.49 and 2.43, 95 % CI 2.17–2.74). Rheumatoid arthritis, COPD, IBD and neurological diseases also significantly increased the risk of non-vertebral, non-hip fractures (aORs 1.23, 1.42, 1.52 and 1.94 respectively). ConclusionSome glucocorticoid requiring diseases were independently associated with an increased risk of fractures. COPD and neurological diseases with both vertebral and non-vertebral fracture risk while RA and IBD were independently associated only with non-vertebral, non-hip fractures.

Deteriorated bone microarchitecture caused by sympathetic overstimulation in pheochromocytoma and paraganglioma.

Despite the potentially destructive effect of sympathetic activity on bone metabolism, its impact on bone microarchitecture, a key determinant of bone quality, has not been thoroughly investigated. This study aims to evaluate the impact of sympathetic activity on bone microarchitecture and bone strength in patients with pheochromocytoma and paraganglioma (PPGL). A cross-sectional study was conducted in 38 PPGL patients (15 males and 23 females). Bone turnover markers serum procollagen type 1 N-terminal propeptide (P1NP) and β-carboxy-terminal crosslinked telopeptide of type 1 collagen (β-CTX) were measured. 24-h urinary adrenaline (24hUE) and 24-h urinary norepinephrine levels (24hUNE) were measured to indicate sympathetic activity. High-resolution peripheral quantitative computed tomography (HR-pQCT) was conducted to evaluate bone microarchitecture in PPGL patients and 76 age-, sex-matched healthy controls (30 males and 46 females). Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (DXA) simultaneously. PPGL patients had a higher level of β-CTX. HR-pQCT assessment revealed that PPGL patients had notably thinner and more sparse trabecular bone (decreased trabecular number and thickness with increased trabecular separation), significantly decreased volume BMD (vBMD), and bone strength at both the radius and tibia compared with healthy controls. The deterioration of Tt.vBMD, Tb.Sp, and Tb.1/N.SD was more pronounced in postmenopausal patients compared with the premenopausal subjects. Moreover, subjects in the highest 24hUNE quartile (Q4) showed markedly lower Tb.N and higher Tb.Sp and Tb.1/N.SD at the tibia than those in the lowest quartile (Q1). Age-related bone loss was also exacerbated in PPGL patients to a certain extent. PPGL patients had significantly deteriorated bone microarchitecture and strength, especially in the trabecular bone, with an increased bone resorption rate. Our findings provide clinical evidence that sympathetic overstimulation may serve as a secondary cause of osteoporosis, especially in subjects with increased sympathetic activity.

THU439 Baby's Coming, Break A Leg! A Case Of Transient Osteoporosis Of The Hip

Abstract Disclosure: A. Khan: None. A. Syeda: None. H.B. Aftab: None. Introduction: Pregnancy-associated osteoporosis (PAO) is a rare condition presenting as fragility fractures usually in the latter part of pregnancy or immediate postpartum period. Vertebral fractures are more commonly reported but femoral fractures have also been described in the literature as a distinct entity: transient osteoporosis of the hip (TOH). We present a case of bilateral (B/L) femoral fractures in a woman during pregnancy and in the postpartum period. Case: A 31-year-old, gravida 1 female developed left leg pain at 26 weeks of gestation. The pain radiated from her left lower back to her left knee. It was severe in intensity resulting in her walking with crutches. Subsequent MRI of the left hip showed subchondral insufficiency fracture of the femoral head with prominent bone marrow edema extending from the head into the femoral neck. She was managed conservatively with non-weight bearing status and oral analgesics. She had an uncomplicated vaginal delivery at 39 weeks of gestation. During the first postpartum week she developed right hip pain. MRI of right hip revealed nondisplaced right femoral head subchondral insufficiency fracture with associated effusion and synovitis. She recovered within the next 3 months with resolution of her pain with conservative management. Other than limited calcium intake in childhood, there were no other identifiable risk factors for osteoporosis. Bone density scan revealed normal Z-scores at the lumbar spine and non-dominant wrist. The hips were not evaluated. Workup for secondary causes of osteoporosis was unremarkable including normal serum calcium, PTH, phosphorus, magnesium, SPEP, tissue transglutaminase antibodies, estradiol, LH, FSH, prolactin levels. However, 24-hour urine calcium level was low at 11 (35-250) mg/24hr. Elevated levels of bone specific alkaline phosphatase and urine N-telopeptide (NTX) were noted at 19.9 (5.3-19.5) mcg/L and 110 (4-64) nM BCE/mM creatinine, respectively. Patient was continued on vitamin D and calcium supplements. She breastfed for the initial 2 months but was advised to stop. At her most recent follow up visit 4 months postpartum patient was doing well. Discussion: TOH is a rare entity, and presentation as B/L femoral fractures is exceedingly rare. During pregnancy and lactation, the skeletal system undergoes bone loss to compensate for the calcium demand of the fetal skeletal system. In TOH, venous stasis from the gravid uterus resulting in bone marrow edema is the proposed mechanism in addition to pregnancy associated bone loss. In our patient, a low 24-hr urine calcium could suggest low calcium intake which could have contributed to the fracture as well. While recurrence of PAO has been described, no recurrence of TOH has been reported in subsequent pregnancies. Our case highlights the importance of keeping this rare entity on the differential in pregnant women presenting with back or hip pain. Presentation: Thursday, June 15, 2023

THU424 A Diagnostic Predictive Model For Secondary Osteoporosis In Patients With Fragility Fracture: A Retrospective Cohort Study In A Tertiary Care Hospital

Abstract Disclosure: P. Phudphong: None. M. Phimphilai: None. W. Manosroi: None. N. Adulkasem: None. T. Kaewchur: None. Introduction: Although primary osteoporosis is the leading etiology of osteoporosis in asymptomatic elderly presenting with fragility fractures, secondary osteoporosis can be accounted for one-third of patients. Establishing whether a fragility fracture is secondary to a specific cause of osteoporosis is crucial for treatment outcomes. This study aimed to develop a simple screening tool for secondary osteoporosis in the elderly who are presented with fragility fractures. Methods: A retrospective cohort study of 456 patients diagnosed with non-traumatic hip and clinical vertebral fractures between January 2017 and July 2022 was conducted. Demographic, clinical, biochemical, and final diagnostic data were retrieved. Potential predictors for secondary osteoporosis were identified via multivariate logistic regression analysis. Subsequently, we developed a predictive model for secondary osteoporosis using the identified potential predictors. Results: This study included 343 females and 113 males with a mean age of 76.9±11.0 years. One hundred and twenty-one patients (26.5%) were diagnosed with secondary osteoporosis. Vitamin D deficiency (71.9%) was the most common cause of secondary osteoporosis, followed by glucocorticoid-induced osteoporosis (23.9%) and primary hyperparathyroidism (9.9%). The developed prediction model for secondary osteoporosis demonstrated an acceptable discriminative ability with an AuROC of 0.75 (95%CI 0.69 to 0.81) using the patient’s age, body mass index (BMI), corrected serum calcium, serum phosphate, thyroid stimulating hormone (TSH) level, and BMI-based FRAX score. With a cut-off level of 0.22, the proposed predictive model revealed a sensitivity of 74.4% and a specificity of 65.8%. Finally, the developed prediction model was derived into a web-based screening tool available at: https://www.calconic.com/calculator-widgets/secondary-osteoporosis-screening-tool/62f7c112d5da86001f8e3a25?layouts=true. Conclusion: A predictive model for screening secondary osteoporosis was constructed using simple clinical and biochemical parameters. This newly developed predictive model may provide clinicians with guidance to perform further advanced investigations for secondary causes of osteoporosis. Presentation: Thursday, June 15, 2023

THU468 Finding An Effective Treatment For Osteoporosis In Gaucher Disease

Abstract Disclosure: C. Lesniak: None. M.S. Akula: None. Background: Gaucher disease is a rare autosomal recessive disorder, leading to a deficiency of the enzyme glucocerebrosidase and accumulation of lipid-laden macrophages and dysfunction of multiple organs. The skeletal system is commonly affected resulting in reduced bone mineral density (BMD), marrow infiltration and bone infarction. Enzyme replacement therapy (ERT) has been a mainstay of treatment, and bisphosphonate therapy has been used to help treat osteoporosis, but newer agents are not well studied in this population. Case Description: The patient is a 62 year old female with a history of Gaucher disease Type 1 (GD1) and osteoporosis, treated with alendronate. She was diagnosed with GD1 in childhood and treated with glucocerebrosidase as ERT. She was diagnosed with osteoporosis in 2018 and started on bisphosphonates after a DXA scan showed a T-score at the lumbar spine of −3.2 and -1.4 at the left hip. She denied bone or back pain and has no history of any osteolytic lesions or osteonecrosis. Workup for secondary causes of osteoporosis was negative. She was taking alendronate 70 mg weekly, calcium 1800 mg daily, and vitamin D 4000 IU daily. Labs showed calcium 9.1 mg/dL, TSH 1.530 uIU/mL, PTH 34 pg/mL, and 25-hydroxy vitamin D 38.7 ng/mL. Repeat DXA scan showed worsening osteoporosis with a T-score at the lumbar spine of −3.4 and left hip of −2.5. As her BMD worsened while on alendronate for 3 years, teriparatide was offered as an alternative treatment. Discussion: Gaucher disease is a rare lysosomal storage disorder affecting multiple organs. Up to 90% of patients with GD1 have bone involvement of some kind. DXA scan should be done soon after diagnosis. Reduced BMD in GD1 is common and is associated with increased fracture risk. ERT has been the main management option to treat bone manifestations with improvement in BMD shown after 3-5 years. After 8 years of treatment with ERT, patients have been shown to reach the BMD of the age and sex matched population. In addition to ERT, calcium and vitamin D3 are recommended to increase BMD. There is no standard of treatment for osteoporosis in Gaucher patients, although bisphosphonates have been shown to improve BMD. Had our patient had early DXA scans, treatment may have been initiated sooner. A single case report showed improvement in BMD with the use of teriparatide after bisphosphonate failure. The efficacy of alternative agents, such as teriparatide and romosumab, in treating osteoporosis in patients with Gaucher disease needs to be further investigated. Presentation: Thursday, June 15, 2023

THU438 A Case Of Pregnancy Associated Osteoporosis

Abstract Disclosure: S. Maradana: None. F. Iqbal: None. M. Safran: None. Background: Pregnancy associated osteoporosis (PAO) is a rare form of osteoporosis that is seen in late pregnancy and early post-partum period. Hip and vertebral body are most involved in PAO. Common clinical manifestation is back pain, and many patients suffer from vertebral fractures and kyphosis causing great physiologic burden and negative impact on quality of life. We report a case of PAO with good response to teriparatide. Clinical case: A 27-year-old female with no significant past medical history presented with severe acute back pain two months after delivery of her second child, whilst still breast feeding. Imaging studies demonstrated acute compression fractures of T12, L1, L2 and L3 vertebrae. She had regular monthly menstrual cycles prior to pregnancy with no previous history of fractures. Her pre pregnancy weight was 135 lbs and she had been physically active, while caring for her older son. Family history is notable for osteoporosis in multiple paternal aunts and maternal grandmother with no family history of fractures. There were no other identifiable risk factors. Evaluation for secondary causes of osteoporosis showed 25-OH vitamin D levels of 23 ng/mL (NL 30-100 ng/mL), TSH 1.72 uIU/mL (NL 0.28-3.8 uIU/mL), PTH 19 pg/mL (NL 14-64 pg/mL), calcium 9.7 mg/dL (NL 8.7-10.7 mg/dL), phosphorus 4 mg/dL (NL 2.5-4.5 mg/dL), tryptase 4 mcg/L (NL <11 mcg/L), alkaline phosphatase 111 U/L (NL 30-115 U/L) and 24-hour urine calcium 168 mg (NL 100-300 mg). Urine immune electrophoresis and serum immunofixation did not show any evidence of monoclonal gammopathy. DEXA scan showed low BMD with Z-score of −4.4 SD in lumbar spine -3.1 in femoral neck. She was diagnosed with PAO. She stopped breast feeding after the diagnosis. As the bone mineral density was very low, she was started on teriparatide along with calcium and vitamin D supplementation. One year after treatment initiation, her DEXA scan showed improved bone mineral density with Z-score of −3.5 in lumbar spine and −1.9 in femoral neck. Her osteoporosis is currently being managed with teriparatide with plan to continue for a total duration of 24 months. Conclusion: PAO is under-recognized and under-reported, with limited available evidence on the management. Spontaneous improvement in BMD is known to occur in 6-12 months after pregnancy and lactation have been completed, although, the addition of anti-resorptive treatment in this setting may result in superior BMD gain compared with calcium and vitamin D supplementation alone. Use of teriparatide has shown to have significant increase in BMD and help with pain relief in PAO. Teriparatide has helped with improving the BMD in our patient. Nevertheless, controlled trials are lacking, and the optimal timing of teriparatide use in these women remains uncertain. Presentation: Thursday, June 15, 2023

THU431 An Interesting Case Of Severe Osteoporosis In A Young Male

Abstract Disclosure: M. Bilbatua: None. M. Deshmukh: None. Background: Systemic Mastocytosis is a rare disorder in which Osteoporosis is seen in about 24% of cases. We describe a rare case of Secondary Osteoporosis in a young man caused by Systemic Mastocytosis. Case presentation: A 32-year-old male with no significant medical history was seen by Endocrinology for evaluation of Osteoporosis. Symptoms started after two episodes of falls which caused persistent pain. A CT scan of thoracic spine revealed chronic anterior wedge compression fracture of T5, T7 and T10 with approximately 5-10% loss of height. DEXA scan demonstrated T-score of -4.2 at L1-L4, T-score of -2.3 at left hip suggestive of severe Osteoporosis. The patient admitted to generalized flushing and itching after taking hot showers as well as intermittent episodes of palpitations. The patient was started on Calcitonin nasal spray daily for pain related to vertebral fracture. Testing for secondary causes of Osteoporosis showed a Total testosterone 410 ng/dL (250-1,100 ng/dL), PTH 16 pg/mL (16 - 77 pg/mL), TSH 1.88 mIU/L (0.40 - 4.50 mIU/L), Phosphorus 4.1 mg/dL (2.5 - 4.5 mg/dL), Magnesium 2 mg/dL (1.5 - 2.5 mg/dL), Alkaline phosphatase 66 U/L (36 - 130 U/L), Vitamin D 25 ng/mL (30 - 100 ng/mL), Calcium 9.3 mg/dL (8.6 - 10.3 mg/dL), Tryptase 64 mcg/L (<11.0 mcg/L), 5-HIAA 24H Ur mg/24H 3 (<=6.0 mg/24 h). Based on this, the patient was seen by Hematology/Oncology for evaluation on elevated tryptase levels. Bone marrow biopsy and aspirate was performed, demonstrating 20% Mast cells positive for CD 117, CD 25, patient was diagnosed with Mastocytosis and treatment with Midostaurin 100 mg PO twice daily and Zometa every 12 weeks was initiated. Improvement of Tryptase was noted within two months of treatment. Discussion: Systemic Mastocytosis is a rare disease often complicated by Osteoporosis of which around 37% of the patients will develop Osteoporotic fractures where Bisphosphonates are effective and have a role in the associated refractory bone pain. The pathophysiological mechanisms leading to osteoporosis in Systemic Mastocytosis are not well understood. Although rare, back pain secondary to osteoporotic vertebral fractures is often the major presenting symptom of Mastocytosis and it should be included in the differential diagnosis of idiopathic osteoporosis due to its significant morbidity. Presentation: Thursday, June 15, 2023

THU448 Multiple Non-traumatic Vertebral Fractures After Discontinuation Of Denosumab

Abstract Disclosure: S. Riahi: None. A.R. Crawford: None. U. Gruntmanis: None. Background: In multiple studies, including a post-hoc analysis of the FREEDOM trial1, an increased risk of vertebral fractures has been demonstrated in patients after discontinuation of denosumab. Clinical Case: A 65-year-old female presented to the endocrinology clinic for evaluation of severe osteoporosis. She was diagnosed with osteoporosis in 2017 after a DXA scan demonstrated a lumbar spine T-score of −3.5. She was started on denosumab therapy by her primary care provider to treat her osteoporosis and received a total of 10 injections over 5 years, during which time she experienced no fractures. Her lumbar spine T-score improved to −2.6 in March of 2021. She received her last injection of denosumab in December of 2021 and was told that she no longer needed denosumab therapy. She began to develop severe pain in her back in October of 2022 and noticed a 3-inch height loss. X-rays done in November of 2022 demonstrated a new compression fracture in L2. Due to persistent debilitating pain, patient had repeat X-rays performed 1 week later which demonstrated multiple age indeterminate compression fractures which MRI was able to confirm at T5, T7, and T9-T12. Repeat DXA scan in December of 2022 demonstrated a lumbar spine T-score of −3.1. Serum C-Telopeptide (CTX) was 1060pg/mL. Patient had adequate calcium and vitamin D intake, and secondary causes of osteoporosis were excluded. Conclusion: This case report highlights the rapid reversibility of the beneficial effects of denosumab on bone density and bone remodeling after discontinuation of the drug (evidenced by the significantly elevated CTX), the importance of close follow up, and the use of transition therapy in patients after discontinuation of denosumab to attenuate the risks associated with stopping the medication. It also places import on the use of MRI imaging, especially in the cases of rebound associated vertebral fractures secondary to denosumab discontinuation2 for those patients in whom you have high suspicion to better characterize compression fractures when x-ray findings are not felt to be sufficient.

THU426 Randomized Controlled Trial Comparing The Efficacy Of Teriparatide, Zoledronate And Denosumab In Postmenopausal Women With Type 2 Diabetes Mellitus At High Risk Of Fragility Fractures: 6-month Interim Analysis Of HR-pQCT Parameters

Abstract Disclosure: R. Pal: None. T.N. Prasad: None. S.K. Bhadada: None. V. Singla: None. S. Ram: None. N. Aggarwal: None. A. Kumar: None. People with type 2 diabetes (T2D) are at high-risk of fragility fractures, however, there are no randomised controlled trials (RCTs) evaluating the efficacy/safety of anti-osteoporosis drugs as a primary endpoint in T2D (1). To address this lacuna, we conducted a pilot prospective, open-labeled, blinded-end point (PROBE) RCT (CTRI/2022/02/039978) wherein consecutive postmenopausal female (≥ 50 years) with T2D (duration ≥ 5 years) were screened. Subjects with HbA1c 7-10%, eGFR > 45 ml/min/1.73 m2 and prior history of vertebral (clinical/morphometric), hip, radius, humeral fragility fracture or at high-risk of fragility fractures [defined as areal bone mineral density (BMD) T-score (adjusted for diabetes) at lumbar spine/femoral neck ≤ -2.5 and high FRAX score] and without any secondary cause of osteoporosis were randomised in staggered fashion in a 1:1:1:1 ratio to receive either daily teriparatide, yearly zoledronate, biannually denosumab (in addition to standard of care, i.e., calcium 1000 mg/day and cholecalciferol 1000 IU/day) or only standard of care (control). The primary end points were change in areal BMD and frequency of incident fractures at 18 months. The secondary end point was change in HR-pQCT parameters measured at distal radius and distal tibia (XtremeCT II, SCANCO Medical AG, Switzerland) at 6 and 18 months.Out of 412 participants who were screened, 104 subjects were randomized to any of the 4 arms. Out of these 104 subjects, 53 have completed 6 months of follow-up (teriparatide n=14, zoledronate n=14, denosumab n=15, control n=10). There were no statistically significant differences in age, HbA1c, eGFR, calcium, phosphate, alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone, procollagen type I N-propeptide (PINP), C-terminal telopeptide (CTX), areal BMD, trabecular bone score (TBS), FRAX score or HR-pQCT parameters between the 4 groups at randomisation. At 6 months, there was no significant difference in HbA1c between the 4 groups; PINP and CTX rise was significantly higher in teriparatide arm compared to zoledronate, denosumab or control arms. With regard to HR-pQCT, there were no statistically significant differences in total [total volumetric BMD (vBMD), bone volume fraction], cortical (vBMD, thickness, porosity, pore diameter), or trabecular (vBMD, thickness, number, separation) bone properties at the distal radius and distal tibia between the 4 arms at 6 months of follow-up. To conclude, zoledronate, denosumab or teriparatide were unable to induce any significant microarchitectural changes than standard of care in postmenopausal women with T2D at high-risk of fragility fractures following 6 months of treatment. Longer duration of treatment and follow-up of the cohort is required to arrive at robust conclusions. Reference: (1) Pal et al., Bone fragility in type 2 diabetes mellitus: a lot left to explore. Nat Rev Endocrinol. 2022;18:651-651 Presentation: Thursday, June 15, 2023

THU603 Bone Fragility In Mild Autonomous Cortisol Secretion: A Cross-Sectional Cohort Study

Abstract Disclosure: C.D. Zhang: None. S. Singh: None. J. Saini: None. M. Suresh: None. K. Thangamuthu: None. R. Nathani: None. A.L. Ebbehøj: None. V. Fell: None. S.J. Achenbach: None. E.J. Atkinson: None. S. Khosla: None. I. Bancos: None. Background: Patients with mild autonomous cortisol secretion (MACS) have higher rates of fractures compared to patients with non-functioning adrenal nodules, but bone mass is typically only modestly reduced. We hypothesized that chronic exposure to mild levels of cortisol excess may lead to a deterioration in bone quality. Objective: To characterize the effect of MACS on bone metabolism and bone microarchitecture, as measured by high-resolution peripheral quantitative computed tomography (HR-pQCT). Methods: In this cross-sectional single-center study, patients with MACS were matched by age, sex, and gonadal status to referent subjects without adrenal nodules. MACS was defined as serum cortisol concentration >1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (1-mg DST), in the absence of a classic Cushingoid phenotype. Those with other known secondary causes of osteoporosis and/or on pharmacologic treatment for low bone mass were excluded. All study participants underwent a bone health interview, blood draw for bone turnover markers, dual-energy x-ray absorptiometry (DXA) scan with trabecular bone score (TBS), and HR-pQCT of the non-dominant radius and tibia. Participants with a recent fracture within 12 months were excluded from the analysis of bone turnover markers. The Kruskal-Wallis test was used to compare measurements between groups. Results: A total of 82 patients with MACS and 82 referent subjects were prospectively enrolled between 1/2019 and 7/2022. The median age of study participants at the time of enrolment was 57 years (interquartile range [IQR], 47-65), and 57 (70%) were women. In the MACS cohort, the median cortisol following 1-mg DST was 3.2 mcg/dL (IQR, 2.3-6.5) with median ACTH of 8.7 pg/mL (IQR, 6.0-14.0) and median DHEA-S of 42.0 mcg/dL (IQR 23.0-68.0). While no differences in bone mineral density (BMD) were observed at any site (lumbar spine, total hip, femoral neck, or distal radius) between the two groups, patients with MACS had decreased TBS (1.374 vs 1.467, P <0.001) and lower osteocalcin concentrations (16.9 vs. 19.7 ng/mL, P = 0.005) than referent subjects without adrenal nodules. On HR-pQCT at the tibia, patients with MACS had significantly reduced trabecular volumetric BMD (151.6 vs 167.4 mg hydroxyapatite/cm3, P = 0.002), trabecular bone volume/tissue volume ratio (0.219 vs 0.237, P = 0.011), and number of trabeculae (1.428 vs 1.506 1/mm, P = 0.045), while trabecular separation (0.707 vs 0.656, P = 0.023) was increased compared to referent subjects. Conclusions: Patients with MACS have altered bone metabolism and microstructural deterioration that is not evident on routine DXA BMD testing. These changes may mediate their increased fracture risk and could serve as biomarkers of cortisol-induced changes in the bone. Presentation: Thursday, June 15, 2023

THU416 Trabecular Bone Score, Bone Mineral Density, And Fractures In Patients Of Chronic Kidney Disease With And Without Diabetes Mellitus

Abstract Disclosure: V. Suryadevara: None. R. Kg: None. A. Prasad: None. V. Sunthoju: None. P. Ps: None. R. Govindarajalou: None. J. Sahoo: None. S. Kamalanathan: None. D. Naik: None. Background and objectives: Chronic kidney disease-mineral bone disease (CKD-MBD) is a common yet neglected long-term complication of CKD. The primary objective of this study was to compare the proportion of patients with low trabecular bone score (TBS) in the CKD patients with diabetes mellitus (CKD-DM) and the CKD patients without DM (CKD-NDM). The secondary objectives were to compare bone mineral density (BMD) and morphometric vertebral fractures (VF) between the two groups. Methods: Patients of CKD with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2, and not initiated on maintenance hemodialysis were recruited in the study. They were classified into the CKD-DM or the CKD-NDM group based on the presence of DM. Both groups were matched for age and gender. A detailed history was taken, and a physical examination was done to rule out secondary causes of osteoporosis. Serum creatinine, electrolytes, 25 hydroxy vitamin [25 (OH)D], and intact parathyroid hormone (iPTH) were analysed. Areal BMD was assessed using Hologic Discovery Wi dual-energy X-ray absorptiometer. TBS was estimated from spine BMD images using TBS iNsight software v 3.1.1 (Medimaps, Geneva). A dorsolumbar spine radiograph was performed to look for morphometric VFs. Results: 306 participants with CKD (153- diabetic and 153 non-diabetic) were included. The baseline characteristics were comparable between the two groups except for a higher BMI [24.13 (21.9-27.5) vs 21.86 (19.7-24.4) kg/m2], higher waist circumference [92.5 (85-99) vs 85 (80-93) cm], higher eGFR [31 (15.5-42.5) vs 25 (13-34) ml/min/1.73m2], lower magnesium [2 (1.8-2.2) vs 2.1 (1.8-2.4) mg/dl], and lower 25(OH)D [28.82 (21.3-38.6) vs 36.11 (28.4-47.3) ng/ml] in the CKD-DM group. The proportion of patients with low bone turnover (iPTH levels < 80 pg/ml) was higher in the CKD-DM group (34.2% vs 27.1%). The proportion of patients with low TBS was similar between the two groups (39.86% vs 41.83%; p=0.727). The BMD at lumbar spine (LS) [0.977 (0.877-1.128) vs 0.945 (0.814-1.148) g/cm2; p=0.219] and distal forearm (FA) [0.689 (0.618-0.736) vs 0.661 (0.576-0.731) g/cm2; p = 0.053] were also comparable between the two groups. However, BMD at femur neck (FN) [0.707 (0.624-0.798) vs 0.665 (0.586-0.768) g/cm2; p=0.012] and total hip (TH) [0.862 (0.760-0.951) vs 0.811 (0.713-0.916) g/cm2; p=0.006] were higher in the CKD-DM group. The prevalence of morphometric VF was similar between the two groups (8.5% vs 5.2%; p=0.258). Conclusion: In this cohort of pre-dialysis stage 3-5 CKD patients, the prevalence of low TBS, BMD at LS and distal FA were similar between the CKD-DM and the CKD-NDM groups. The BMD at FN and TH was higher in CKD with DM compared to CKD without DM. Presentation: Thursday, June 15, 2023

Glucocorticoid-induced osteoporosis: an overview with focus on its prevention and management.

The widespread use of glucocorticoids (GCs) contributes to the effective management of several diseases and conditions. However, it comes at a price in the case of the bones causing glucocorticoid-induced osteoporosis (GIOP), the most common cause of secondary osteoporosis and fractures. Several scientific societies have issued comprehensive guidelines on the optimal management of patients receiving GCs with the aim of providing answers to three fundamental questions, namely, whom to treat, when to treat, and how to treat. Both common ground and different approaches exist among them. General preventive measures should start along with GC initiation, and the duration of GC therapy should be limited to the minimal effective range. A pre-existing fracture, age, gender, menopausal status, dose, and duration of GC treatment are key factors in the decision to initiate antiosteoporotic medication. Oral bisphosphonates are typically regarded as the first-line treatment choice for GIOP partly due to their cost-effectiveness. Denosumab is another valid option, but an "exit strategy" should be considered before its initiation due to the risk of rebound-associated vertebral fractures upon its discontinuation. Since impaired bone formation represents the main mechanism by which GCs negatively affect skeletal health, osteoanabolic therapies appear to be pathophysiologically the more appropriate and appealing option, although cost considerations currently limit their use to selected severe cases. Regardless of the agent selected to mitigate the impact of GCs on the skeleton, what is most crucial is that the treating physician correctly stratifies the risk and intervenes at the right time.

Comparative Effectiveness of Therapeutic Interventions in Pregnancy and Lactation-Associated Osteoporosis: A Systematic Review and Meta-analysis.

The optimal management of pregnancy and lactation-associated osteoporosis (PLO) has not been designated. To systematically review the best available evidence regarding the effect of different therapeutic interventions on bone mineral density (BMD) and risk of fractures in these patients. A comprehensive search was conducted in PubMed/Scopus databases until December 20, 2022. Data were expressed as weighted mean difference (WMD) with 95% CI. The I2 index was employed for heterogeneity. Studies conducted in women with PLO who received any antiosteoporosis therapy were included. Studies including women with secondary causes of osteoporosis or with transient osteoporosis of the hip were excluded. Data extraction was independently completed by 2 researchers. Sixty-six studies were included in the qualitative analysis (n = 451 [follow-up time range 6-264 months; age range 19-42 years]). The increase in lumbar spine (LS) BMD with calcium/vitamin D (CaD), bisphosphonates, and teriparatide was 2.0% to 7.5%, 5.0% to 41.5%, and 8.0% to 24.4% at 12 months, and 11.0% to 12.2%, 10.2% to 171.9%, and 24.1% to 32.9% at 24 months, respectively. Femoral neck (FN) BMD increased by 6.1% with CaD, and by 0.7% to 18% and 8.4% to 18.6% with bisphosphonates and teriparatide (18-24 months), respectively. Meta-analysis was performed for 2 interventional studies only. Teriparatide induced a greater increase in LS and FN BMD than CaD (WMD 11.5%, 95% CI 4.9-18.0%, I2 50.9%, and 5.4%, 95% CI 1.2-9.6%, I2 8.1%, respectively). Due to high heterogeneity and lack of robust comparative data, no safe conclusions can be made regarding the optimal therapeutic intervention in women with PLO.

A diagnostic predictive model for secondary osteoporosis in patients with fragility fracture: a retrospective cohort study in a tertiary care hospital.

Establishing whether a fragility fracture is secondary to a specific cause of osteoporosis is crucial for treatment outcomes. Therefore, this study aimed to develop a simple screening tool for secondary osteoporosis in the elderly initially presented with fragility fractures. A retrospective cohort study including 456 patients with fragility hip and vertebral fractures that occurred between January 2017 and July 2022 was conducted. Demographic, clinical, biochemical, and final diagnostic data were retrieved. Potential predictors for secondary osteoporosis were determined by multivariable logistic regression analysis, and a predictive model for secondary osteoporosis was subsequently developed using identified potential predictors. This study included 343 females and 113 males with a mean age of 76.9 ± 11.0 years. One hundred and twenty-one patients (26.5%) were diagnosed with secondary osteoporosis. Vitamin D deficiency (71.9%) was the most common cause of secondary osteoporosis, followed by glucocorticoid-induced osteoporosis (23.9%) and primary hyperparathyroidism (9.9%). The potential predictors for secondary osteoporosis included in the predictive model were age, body mass index (BMI), corrected calcium, phosphate, thyroid stimulating hormone, and a 10-year probability of hip fractures calculated by BMI-based FRAX®. With a cut-off level of 0.22, the proposed predictive model has an AuROC of 0.75 (95% CI 0.69 to 0.81) with a sensitivity of 77%, a specificity of 66%, and an accuracy of 68.9%. A predictive model for screening secondary osteoporosis was constructed using simple clinical and biochemical parameters. This newly developed predictive model may provide clinicians with guidance to perform further advanced investigations for secondary causes of osteoporosis.

Dendrobium offificinale polysaccharides prevents glucocorticoids-induced osteoporosis by destabilizing KEAP1-NRF2 interaction

Glucocorticoid-induced osteoporosis (GIOP) represents the foremost cause of secondary osteoporosis and fragility fractures. Novel therapeutic strategies for GIOP are needed, with improved safety profiles and reduced costs compared to current options. Dendrobium officinale (D. officinale) is a traditional Chinese medicine that has been reported to have beneficial effects on bone metabolism. Here, we sought to investigate the impacts of D. officinale polysaccharides (DOP), the main active constituents of D. officinale, on GIOP in vivo models and dexamethasone (DEX)-treated osteoblast lineage cells. We found that low concentrations of DOP are relatively safe in vitro and in vivo, respectively. Importantly, we found that DOP treatment significantly inhibited DEX-induced osteoporosis in two in vivo models, zebrafish and mice, while boosting osteogenic differentiation of hBMSCs exposed to DEX. Futhermore, our data reveal that DOP elevates nuclear Nrf2 levels under DEX treatment, by suppressing of Nrf2 ubiquitination. Leveraging Keap1b knockout zebrafish and RNAi approach, we demonstrated that DOP disrupts the association of Nrf2/Keap1, resulting in the inhibition of Nrf2 ubiquitination. Taken together, these results illuminate that DOP stimulates osteogenesis in the presence of DEX by destabilizing the Nrf2/Keap1 interaction. These findings suggest that DOP may serve as a novel drug against osteoporosis caused by glucocorticoids.

The implicit reason of secondary osteoporosis: real clinical case

This article presents a non-standard clinical case of non-obvious causes of secondary osteoporosis in the routine practice of an outpatient and inpatient endocrinologist. This work demonstrates a rather rare situation, including the identification of atypical clinical manifestations of osteoporosis in a patient, namely the presence of a young man with complaints of general weakness, severe pain in the spine, forcing daily use of non-steroidal anti-inflammatory drugs, decreased motor activity, and laboratory indicators such as hypercalcemia, hypercalciuria against the background of reference values of parathyroid hormone, hyperproteinemia and increased ESR. Taking into account the clinical picture described above, an integral part of a further correct diagnostic search is the exclusion of endocrine diseases that cause a decrease in bone mineral density. In parallel, the initiated prescription of pathogenetically based treatment of secondary osteoporosis is an important component of this disease. The use of such a multidisciplinary approach led to timely verification of the underlying oncohematological disease and routing the patient to a specialized hospital and made it possible to prevent irreversible changes associated with a critical decrease in bone mineral density and improve the patient’s quality of life.

Orcinol glucoside targeted p38 as an agonist to promote osteogenesis and protect glucocorticoid-induced osteoporosis

BackgroundGlucocorticoids (GC)-induced osteoporosis (GIOP) is the most common cause of secondary osteoporosis, which leads to an increased risk of fracture in patients. The inhibition of the osteoblast effect is one of the main pathological characteristics of GIOP, but without effective drugs on treatment. PurposeThe aim of this study was to investigate the potential effects of orcinol glucoside (OG) on osteoblast cells and GIOP mice, as well as the mechanism of the underlying molecular target protein of OG both in vitro osteoblast cell and in vivo GIOP mice model. MethodsGIOP mice were used to determine the effect of OG on bone density and bone formation. Then, a cellular thermal shift assay coupled with mass spectrometry (CETSA-MS) method was used to identify the target of OG. Surface plasmon resonance (SPR), enzyme activity assay, molecular docking, and molecular dynamics were used to detect the affinity, activity, and binding site between OG and its target, respectively. Finally, the anti-osteoporosis effect of OG through the target signal pathway was investigated in vitro osteoblast cell and in vivo GIOP mice model. ResultsOG treatment increased bone mineral density (BMD) in GIOP mice and effectively promoted osteoblast proliferation, osteogenic differentiation, and mineralization in vitro. The CETSA-MS result showed that the target of OG acting on the osteoblast is the p38 protein. SPR, molecular docking assay and enzyme activity assay showed that OG could direct bind to the p38 protein and is a p38 agonist. The cellular study found that OG could promote p38 phosphorylation and upregulate the proteins expression of its downstream osteogenic (Runx2, Osx, Collagen Ⅰ, Dlx5). Meanwhile, it could also inhibit the nuclear transport of GR by increasing the phosphorylation site at GR226 in osteoblast cell. In vivo GIOP mice experiment further confirmed that OG could prevent bone loss in the GIOP mice model through promoting p38 activity as well as its downstream proteins expression and activity. ConclusionsThis study has established that OG could promote osteoblast activity and revise the bone loss in GIOP mice by direct binding to the p38 protein and is a p38 agonist to improve its downstream signaling, which has great potential in GIOP treatment for targeting p38. This is the first report to identify OG anti-osteoporosis targets using a label-free strategy (CETSA-MS).

Mastocytose als oorzaak van osteoporotische fracturen: casusbespreking en literatuurstudie

Mastocytosis as a cause of osteoporotic fractures: a case report and literature review Systemic mastocytosis is a rare cause of secondary osteoporosis. Mastocytosis is a myeloproliferatic disease characterized by abnormal growth and proliferation of mast cells. The disease is associated with activating KIT mutations. There are 2 major types of mastocytosis: cutaneous mastocytosis and systemic mastocytosis with extracutaneous infiltration. Systemic mastocytosis needs to be considered in the differential diagnosis of unexplained osteoporosis, unexplained spinal fractures (especially in men and premenopausal women) and in patients with osteoporosis with severe bone pain. Bone involvement is one of the most frequent expressions of systemic mastocytosis, especially in adults. The clinical presentation is diverse: from osteoporosis with fragility fractures and poorly localized bone pain to asymptomatic osteolytic and/or focal sclerotic lesions and diffuse osteosclerosis. Osteoporosis in patients with systemic mastocytosis is caused by neoplastic infiltration or, more likely, local release of mediators. Screening for mastocytosis is possible by determining the serum basal tryptase and searching for a p.D816V KIT mutation, but the final diagnosis requires a bone marrow examination. The first-line treatment of osteoporosis secondary to mastocytosis consists of bisphosphonates and denosumab. Teriparatide can be considered in patients with new vertebral fractures under treatment with antiresorptive therapy, but more research is needed to evaluate its effectivity and safety. In case of refractory osteoporosis caused by mastocytosis, cytoreductive therapy, whether or not in combination with bisphosphonates, can be administered. In this article, the authors report a case of a 48-year-old patient with osteoporosis as the first manifestation of underlying mastocytosis. A literature review was performed to describe the etiology, pathophysiology, diagnostic process and treatment options of bone involvement in patients with mastocytosis.

Trabecular bone score and bone mineral density as indices of skeletal fragility in endogenous Cushing's syndrome.

Endogenous Cushing's syndrome (CS) is a known cause of secondary osteoporosis. Vertebral fractures (VFs) in endogenous CS may occur despite normal bone mineral density (BMD). Trabecular bone score (TBS) is a relatively new, non-invasive technique to assess bone microarchitecture. The objective of our study was to analyse the BMD and bone microarchitecture using TBS in endogenous CS and compare it with a group of age and sex-matched healthy controls, and also analyse the factors predicting BMD and TBS. Cross-sectional study of cases and controls. We included 40 female patients with overt endogenous CS, out of which 32 were adrenocorticotropic hormone (ACTH)-dependent CS and 8 were ACTH-independent. We also included 40 healthy, female controls. Both patients and controls were subjected to an assessment of biochemical parameters and BMD and TBS. Patients with endogenous CS had significantly lower BMD at the lumbar spine, femoral neck, and total hip and significantly lower TBS than healthy controls (all p < .001), while no significant difference was noted in the distal radius BMD (p = .055). In endogenous CS, a large proportion of patients, n = 13 (32.5%) had normal BMD for age (BMD Z-score ≥ -2.0) with low TBS (L1 -L4 TBS ≤ 1.34). TBS correlated negatively with HbA1c (p = .006), and positively with serum T4 (p = .027). TBS should be considered an important complementary tool in addition to BMD for the routine assessment of skeletal health in CS.