Urinary NTX Research Articles

7686 A Case Of A 66-Year-Old Male With Systemic Macrocytosis Complicated By Osteoporosis

Abstract Disclosure: J.M. Gri: None. M. Hillhouse: None. P. madhavan: None. Background: Osteoporosis in men is underestimated and warrants investigation for secondary causes of osteoporosis. Systemic mastocytosis is a rare secondary cause of osteoporosis. Clinical Case: This is a 66-year-old male with a past medical history of severe persistent asthma, eczema, hypertension, GERD with esophagitis, basal cell carcinoma, and systemic mastocytosis (diagnosed in 2010). Family history was significant for lung cancer in both of his parents. Patient was first noted to have hyperpigmented skin lesions on his legs, trunk and upper extremities in the early 1990s. The spots were biopsied and he was diagnosed with urticaria pigmentosa in 1998. Due to persistent symptoms of facial flushing and soft stool, he was referred to Hematology and was started on antihistamines. He later underwent a bone marrow biopsy in 2010 which showed multifocal mast cell aggregates but normal trilineage hematopoiesis. He endorsed back pain shortly after his diagnosis and a DXA scan was completed. The DXA scan showed osteopenia of the spine T score of -1.8, BMD 0.999 mg/mm3 and normal bone density in bilateral hips. He had no history of fractures. He was started on alendronate and remained on the medication from 2012 to 2015. It was stopped due to intolerable symptoms of acid reflux and he required proton pump inhibitors. DXA scan in 2017 showed normal bone density of the hips and osteopenia of the lumbar spine (T score -1.2). DXA scan in 2022 showed a decrease in spine BMD by 6% (T score -1.8) from 2017 to 2022 but unchanged from 2010. Hip bone mineral density was normal but decreased by 10% since 2010 and by 6% since 2017. Labs obtained in May 2022 showed normal serum electrophoresis, normal urine calcium and creatinine ratio, calcium and vitamin D level and urine NTX of 41 nM BCE/mM (21-83) and bone specific alkaline phosphatase level of 31.5 U/L (15-41.3). After discussion with the patient, conservative management with calcium, vitamin D and exercise has been implemented along with close follow up. Should the patient’s bone turnover markers increase or fracture risk increase, additional antiresorptive therapy will be initiated. Conclusion: This case study highlights the importance of screening for osteoporosis in patients with systemic macrocytosis. As this patient was diagnosed with osteopenia at age 53, this case also emphasizes the importance of early screening in both women and men with this rare condition. Presentation: 6/3/2024

Caffeine and Ovariectomy Debilitate Bone Health in Rats on Calcium-deficient Diet.

This study investigated the effects of ovariectomy and caffeine intake on bone health in rats on calcium-deficient diet. Forty adults female Wistar rats were divided into 4 groups in a 2x2 factorial design: Ovary (OVX/SHAM) and Caffeine (placebo/caffeine). The animals were housed in individual cages for 8 weeks, receiving 18-20g of AIN-93M diet per day, containing 50% of the daily recommended intake of calcium. The rats underwent ovariectomy (OVX) or laparotomy (SHAM) surgery. Caffeine groups received 6mg of caffeine/kg/day. After euthanasia, the tibia and femur were dissected to determine the calcium content and bone fracture strength, respectively. Blood sample was collected to determine serum Ostase. 24-hour urine was analyzed for excreted calcium and NTx. Reduced bone fracture strength and calcium content were observed in OVX and Caffeine groups. When observed separately, OVX group showed increased urinary NTx and lower bone weight, blood ostase, and urinary calcium. Caffeine groups showed elevated urinary calcium. There was a positive correlation between bone fracture strength and calcium content. NTx correlated negatively with bone calcium, fracture strength and thickness. In conclusion, both OVX and caffeine intake debilitate bone health in rats on calcium-deficient diet.

FRI683 Every Dose Counts: Response To Half The Recommended Dose Of Romosozumab

Abstract Disclosure: B.P. Ramchandani: None. F.S. Mirza: None. Introduction: Romosozumab (RSB) is a monoclonal antibody that inhibits sclerostin, increases bone formation and decreases bone resorption. It was approved by FDA in 2019 at a dose of 210 mg monthly for 1 year, followed by an anti-resorptive medication. We present a case of a 76 y.o. female with severe osteoporosis and history of intolerance to multiple medications, who was given half the monthly recommended dose of Romo due to extreme concern about side effects. We hereby report the response of her bone density to the treatment. Case Description: A 76-year-old female with history of primary biliary cirrhosis, Sjogren’s syndrome, hemorrhagic duodenal ulcer, s/p subtotal gastrectomy in 1962 presented for evaluation of severe osteoporosis. Fracture history was significant for T11 compression fracture in 2020 requiring kyphoplasty, and a T10 inferior endplate compression fracture requiring vertebroplasty in 2022. Osteoporosis was first diagnosed in 2005. She was intolerant of teriparatide in 2005 (stopped after six months due to nausea, hypercalcemia, cramps, pain in extremities and fatigue). Zoledronic acid (ZA) was administered in 2006 and 2008. Baseline urine telopeptide cross-links (NTx) was low at 18 which decreased to 10 while on ZA and further infusions were held. She declined denosumab and teriparatide was tried again in 2013 that she did not tolerate. She received ZA again in 2016. BMD did not improve on ZA and she declined further infusions. She was physically active and walked daily and was taking calcium citrate, vitamin D and ursodiol during this time. On examination, she was frail and elderly, with BMI of 16.6 mg/kg2. She had mild kyphoscoliosis of the spine with no spinal or paraspinal tenderness. Remainder of the exam was unremarkable. Laboratory evaluation showed normal serum calcium (9.5 mg/dl), albumin (4.1g/dl), Vit D 25-OH (36 mg/ml), bone specific alkaline phosphatase of 22.7 U/L and urine NTx of 23 nm BCE/mm creatinine. Bone density (BMD) in January 2022 showed lumbar spine (LS) BMD of 0.613 g/cm2 (T-score −4.7) and a total hip BMD of 0.575 g/cm2 (T-score −3.4). She was reluctant to consider any medications due to concern about side effects, but finally agreed to a trial of RSB at half the recommended dose at 105 mg monthly for 12 months. DXA scan a year later showed 17% increase in LS BMD (0.715 g/cm2, T-score -3.9), with stable total hip BMD. She has been transitioned to denosumab, which she was now agreeable to take. Discussion: Our patient showed significant improvement in BMD with half the recommended dose of RSB, comparable to the increase in LS BMD reported in phase 3 trials. She was petite and her weight-based dose was just short of 3 mg/kg body weight. Phase 1 and 2 studies had tried weight based and smaller doses of Romo and showed improvement in BMD. This case highlights the need for additional studies with weight-based dosing of RSB, which may reduce the cost of treatment. Presentation: Friday, June 16, 2023

Preliminary study of bone biomarkers in elite female ballet dancers

Elite female ballet dancers are at high-risk of bone stress injuries (BSI) due to high-levels of weight-bearing exercise causing micro-cracks to form in the bone. The consistently high volumes of weight-bearing exercise may lead to a low BMI which reduces oestrogen levels by suppressing the gonadotrophin axis. The combination of high-levels of weight-bearing exercise and low oestrogen may be associated with increased bone remodelling. Investigating the relationship between exercise, BMI, oestrogen, and bone remodelling is crucial for developing prevention and management strategies for BSI. We conducted a pilot study of 4 weeks in a group of elite female professional ballet dancers and in female controls: the study subjects were monitored for self-reported weekly exercise, BMI, urinary oestrogen metabolites (2OHE1 and 16OHE1) and urinary NTX, a marker of bone resorption and proxy for remodelling. Measurements were collected at baseline, week 2 and 4. Dancers exhibited significantly higher hours of exercise per week (p = 0.004), and a BMI significantly lower (p = 0.030) than that of age-matched controls. In contrast, the levels of oestrogen metabolites (p = 0.050) and NTX (p = 0.460) were comparable in the two groups. Using NTX as a biomarker of bone remodelling, these results suggest that despite intense weight-bearing exercise, ballet dancers may not undergo higher bone remodelling than controls. The resulting insufficiency of bone remodelling may increase the risk of BSI because micro-cracks might accumulate in the bone faster than damaged tissue could be replaced. Based on these findings, larger studies will be designed to assess the effect of bone remodelling on BSI risk and recovery in professional ballet dancers, to develop a platform of prevention and treatment strategies including screening programmes to identify dancers at risk.

Clinical Outcomes of Switching from Zoledronic Acid to Denosumab for the Management of Severe Bone Metastasis from Hepatocellular Carcinoma: A Single-Center, Open-Label, Prospective Intervention Trial.

Zoledronic acid reduces the risk of bone metastasis, but denosumab is a better option for treating bone metastases. However, few studies have evaluated the use of denosumab to treat bone metastasis originating from hepatocellular carcinoma. This study aimed to assess the clinical outcomes of switching from zoledronic acid to denosumab for treating bone metastasis in patients with hepatocellular carcinoma. This prospective study enrolled 10 patients with HCC and bone metastases. The levels of type 1 collagen cross-linked N-telopeptide (NTx) and tumor growth remained abnormal in these patients despite administration of zoledronic acid for over 3 months. We switched from zoledronic acid to 120 mg denosumab every 4 weeks and evaluated the clinical outcomes, including changes in the NTx level, pain level, and activities of daily living, as well as adverse events, after each administration. Urinary NTx clearance was normal in all patients. The average urinary NTx clearance increased from 13.2 to 21.2 nmol BCE/nmol · Cre (P = 0.54) after the switch to denosumab. Serum NTx levels were abnormal in all cases. The serum NTx level decreased from 142 nmol BCE/L to 126 nmol BCE/L (P = 0.56). The answers to questionnaires on pain and activities of daily living did not change significantly. Some patients showed elevated transaminase levels, but this was not due to the drug switch. Switching to denosumab did not show a significant change of the pain and activity of daily living for the patients with severe bone metastasis from hepatocellular carcinoma, in whom the efficacy of zoledronic acid was limited.

Changes in bone mineral density in unconscious immobile stroke patients from the acute to chronic phases of brain diseases

ObjectivesDecreased bone mineral density (BMD) is observed in immobile stroke patients. But it is not clarified yet how rapidly BMD reduction occurs or what the most influencing factor to BMD loss is. MethodsBMDs in the lumbar vertebrae and the proximal femur of the paralyzed side were measured in 100 immobile stroke patients at 1 week (0 month), 1 month, and 2 months after admission. The levels of serum calcium, phosphorous, 25-hydroxyvitamin D, and urine cross-linked N-telopeptide of type I collagen (NTx) were also measured. ResultsThe average age of patients was 75.0 ± 11.4 years (31–94 years). No BMD reduction was identified in the lumbar vertebrae in 2 months; however, BMD in the femur significantly decreased in 2 months in female patients (P < 0.05). Serum calcium and phosphorous levels remained within the normal range during hospitalization, and 25-hydroxyvitamin D value rose in 2 months. Urine NTx significantly increased in both males and females in 2 months (male: P < 0.05, female: P < 0.01). ConclusionsWhile there was no significant change in lumbar spine BMD in the 2 month period of immobilization after stroke, BMD in the proximal femur showed a significant reduction, particularly in women. The differential loss of BMD in the 2 regions of interest could possibly be due to the physical forces acting on different body parts during mobilization and nutritional factors. More studies are needed with larger study samples and prolonged follow-up to check the accuracy of these observations.

Strontium-89 plus zoledronic acid versus zoledronic acid for patients with painful bone metastatic breast cancer

β-ray strontium-89 (Sr-89) intra-irradiation therapy has been approved and clinically used to reduce bone metastasis pain not alleviated by bone-modifying agents, external radiation, and analgesic agents. We examined the efficacy of zoledronic acid (ZOL) and Sr-89 combination therapy compared with ZOL alone in breast cancer patients with bone metastases. A randomized controlled trial was conducted on breast cancer patients with bone metastasis to compare the efficacy between ZOL monotherapy and ZOL plus Sr-89 combination therapy. The primary endpoints were changes in urinary NTX levels at 13weeks and brief pain inventory scores. The secondary endpoints were analgesic drug usages, response rates, changes in bone metabolism markers, quality of life, and adverse event rates. Thirty of the planned 60 cases were randomly assigned to ZOL alone or ZOL + Sr-89. There were no significant differences in the changes in urinary NTX levels between the 2 groups (P = 0.365). There was no consistent difference in the pain score changes between the 2 groups. Sr-89 addition to ZOL slightly reduced the white blood cell and platelet counts. However, all adverse events were Grade 1. Safety and analgesic drug dose reduction were more evident in ZOL + Sr-89. This trial showed the lack of benefits from Sr-89 addition to ZOL for breast cancer patients with painful bone metastases. However, safety and analgesic drug dose reduction were more evident in ZOL + Sr-89, indicating its potential for pain control. Sr-89 therapy is safe, thus more effective radiopharmaceuticals are anticipated.

Efficacy and Safety of Oral Ibandronate versus Intravenous Zoledronic Acid on Bone Metabolism and Bone Mineral Density in Postmenopausal Japanese Women with Osteoporosis.

There are no published clinical reports comparing ibandronate (IBN) treatment and zoledronic acid (ZOL) treatment in Japanese postmenopausal osteoporotic patients. This investigation therefore compared the efficacy and safety of the drugs on improving bone metabolism and bone mineral density (BMD) in Japanese postmenopausal women with primary osteoporosis. Eighty-two treatment-naïve primary osteoporotic female patients were randomly divided into IBN-treated or ZOL-treated groups. Bone turnover markers and BMD were examined immediately prior to treatment (baseline) and at 6, 12, 18, 24, and 30 months of therapy. Compared with baseline levels, the values of type 1 procollagen N-terminal propeptide, bone-specific alkaline phosphatase (BAP), urinary type-I collagen amino-terminal telopeptide (NTX), and tartrate-resistant acid phosphatase 5b were all significantly decreased at every time point in both groups apart from BAP at 30 months in the ZOL group, urinary NTX at 12 months in the ZOL group and at 24 and 30 months in both groups. Lumbar BMD values were significantly increased at 6, 12, 18, and 24 months in the IBN group and at 6 and 12 months in the ZOL group compared with pre-treatment levels. Hip BMD values were also significantly increased at 6, 12, 18, and 24 months in the IBN group and at 6, 12, and 18 months in the ZOL group compared with baseline values. The percentage changes of hip BMD at 18 and 24 months in the ZOL group were significantly higher than those in the IBN group (both p < 0.05). No remarkable adverse events were noted in either group. In conclusion, both IBN and ZOL significantly and safely improved bone turnover markers and BMD during 30 months of treatment in Japanese osteoporosis patients. The ZOL group tended to exhibit greater gains in BMD as compared with the IBN group, which merits further investigation.

Low serum osteocalcin levels are associated with diabetes mellitus in glucocorticoid treated patients.

Osteocalcin (OC) is involved in the regulation of glucose homeostasis. Glucocorticoid (GC) treatment is associated with impaired osteoblast function, decreased OC levels, and the development and/or worsening of pre-existing diabetes mellitus (DM). Whether decreased OC levels in GC-treated subjects contribute to DM is not well known. The aim of this study was to analyse whether OC levels in GC-treated patients are associated with the presence of DM. One hundred twenty-seven patients (aged 61.5 ± 17.9years) on GC treatment were included. GC dose, treatment duration, presence of DM and bone formation (OC, bone ALP, PINP) and resorption markers (urinary NTX, serum CTX) were analysed. The cut-offs of each bone turnover marker (BTM) for the presence of DM were evaluated and optimised with the Youden index and included in the logistic regression analysis. Among the patients, 17.3% presented DM. No differences were observed in GC dose or duration or the presence of fractures. Diabetics showed lower levels of OC (7.57 ± 1.01 vs. 11.56 ± 1; p < 0.001), PINP (21.48 ± 1.01 vs. 28.39 ± 1; p = 0.0048), NTX (24.91 ± 1.01 vs. 31.7 ± 1; p = 0.036) and CTX (0.2 ± 1.01 vs. 0.3 ± 1; p = 0.0016). The discriminating BTM cut-offs for DM presence were < 9.25ng/mL for OC, < 24ng/mL for PINP, < 27.5nMol/mM for NTX and < 0.25ng/mL for CTX. In a multivariate logistic regression model adjusted for GC dose, BMI, age and the above four BTMs, only OC remained independently associated with DM presence. Thus, in a model adjusted for GC dose, BMI and age, OC was significantly associated with DM (OR: 6.1; 95%CI 1.87-19.89; p = 0.001). Decreased OC levels in GC-treated patients are associated with increased odds of DM, and only OC was independently associated with DM in a model including four BTMs.

Retraction Note: Comparison of the effect of alendronate on lumbar bone mineral density and bone turnover in men and postmenopausal women with osteoporosis.

The purpose of the present study was to compare the effect of alendronate treatment on lumbar bone mineral density (BMD) and bone turnover in men and postmenopausal women with osteoporosis. Sixty men with primary or secondary osteoporosis and 318 women with postmenopausal osteoporosis were treated with alendronate. The primary end points were lumbar BMD and urinary cross-linked N-terminal telopeptides of type I collagen (NTX) and serum alkaline phosphatase (ALP) levels. The secondary end point was the incidence of vertebral and nonvertebral fractures. Forty-seven (78.3%) men and 254 (79.9%) women who could complete the 12-month trial were analyzed. The mean ages of men and postmenopausal women were 69.1 and 70.4 years, respectively. Both men and postmenopausal women showed higher levels of urinary NTX as compared with normal range of premenopausal women. Alendronate treatment decreased urinary NTX level by 39.2% in men and 45.4% in postmenopausal women at 3 months and serum ALP level by 17.8 and 21.0%, respectively, at 12 months. Following reduction in bone turnover markers, lumbar BMD increased 5.8 and 7.6% in men and postmenopausal women, respectively, at 12 months. Reduction in urinary NTX level and increase in lumbar BMD were smaller in men than in postmenopausal women. The incidence of vertebral and nonvertebral fractures was 10.6 and 8.5%, respectively, in men and 8.3 and 7.5%, respectively, in postmenopausal women, with no significant difference in these incidences between them. These results suggested that alendronate treatment effectively increased lumbar BMD from baseline in men with primary or secondary osteoporosis following reduction in bone turnover, although its efficacy did not appear to be greater than in postmenopausal women with osteoporosis.

Changing trends in lipid profile and biomarkers of renal function and bone metabolism before and after switching from tenofovir disoproxil fumarate to tenofovir alafenamide: a prospective observational study

BackgroundAntiretrovirals, including tenofovir, can suppress human immunodeficiency virus (HIV) infection but cannot completely eradicate it. Patients with HIV infection are administered antiretroviral drugs over a long term; thus, managing consequent adverse drug reactions, such as renal dysfunction and bone mineral loss, is important. Currently, highly sensitive biomarkers that can detect adverse drug reactions early have not been well studied.MethodsThis single-center, prospective, observational study explored changes in the biomarkers of renal function, bone metabolism, and lipid profile before and after switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in patients with HIV infection.ResultsAll 31 enrolled patients had been treated with antiretrovirals for more than 5 years. The rate of proteinuria decreased significantly after starting TAF-containing antiretroviral regimen. The urinary liver-type fatty acid binding protein (L-FABP)/creatinine ratio was significantly decreased at 3 and 6 months after switching to TAF compared with that before switching to TAF (− 0.5 μg/g Cr at 3 months, and − 0.8 μg/g Cr at 6 months; p < 005 for both at 3 and 6 months). The urinary N-terminal telopeptide (NTx)/creatinine ratio decreased over the study period, and the ratios were significantly different between 3 and 6 months (− 11 nmol/mmol Cr at 3 months, − 15.2 nmol/mmol Cr at 6 months; p = 0.0069 at 3 months, p < 0.0001 at 6 months). Low density lipoprotein-cholesterol level significantly increased at 3 (+ 26 mg/dL) and 6 months (+ 13 mg/dL) compared with that at the baseline (p < 0.0001).ConclusionsSwitching from TDF to TAF decreased the levels of renal and bone biomarkers, such as urinary L-FABP and NTx, but increased low density lipoprotein-cholesterol levels. Future studies should evaluate if these biomarkers, such as urinary L-FABP and NTx, truly detect serious adverse drug reactions early.

Response of Severe Osteomalacia to High Dose Vitamin D3 Replacement in a Patient With Ulcerative Colitis and Liver Transplantation on Immunosuppressive Therapy

Background: Bone disease is common in inflammatory bowel disease (IBD), more frequently in Crohn’s disease than ulcerative colitis (UC). We present the case of a patient with prior history of ulcerative colitis with severe 25 OH vitamin D deficiency and metabolic bone disease. Case: 67 year old male with h/o ulcerative colitis, colon cancer s/p proctocolectomy and ileostomy, chemo-radiation, h/o primary sclerosing cholangitis (PSC) and orthotopic liver transplantation (OLT) 20 years prior presented with presented with severe muscle aches, severe limitation in mobility and severe vitamin D deficiency. He had been on chronic prednisone and tacrolimus, mycophenolate. Three years after OLT, he had fragility fractures at different times in both hips requiring hip arthroplasty. Labs were significant for persistently elevated alkaline phosphatase (ALP) up to 1569 U/L for last 10 years, bone specific ALP at 423.6 mcg/L, Calcium 9 mg/dl, phosphorus 2 mg/dl, 25 OH vitamin D was 4 ng/ml, 1, 25-hydroxy vitamin D (25-OHD) was 34 ng/ml, PTH was 189 pg/ml, urine calcium/creatinine ratio was 50 mg/g and urine NTX at 223 nM BCE/mM. Celiac screen was negative and tacrolimus levels were within normal range. Patient had extensive workup by gastroenterology for elevated ALP including three liver biopsies which were unrevealing. A bone scan showed increased uptake in thoracic region and metaphyses of large joints. A diagnosis of osteomalacia and secondary hyperparathyroidism was made and he was started on high dose vitamin D gradually increased to 8000 units thrice a day. Within few weeks, he noted marked improvement in mobility, bone pain and need for pain medications. In few months, BSAP decreased to 144.9 mcg/l, NTX and PTH also improved. 25 OH has also increased slightly to 13. He continues on high dose vitamin D and 1200mg of calcium daily. Discussion: Our patient likely had severe osteomalacia due to prolonged vitamin D deficiency, caused by multiple etiologies. Firstly, poor absorption in UC might lower 25-OHD levels. Secondly CYP3A enzymes are involved in the metabolism of calcineurin inhibitor tacrolimus as well as vitamin D, this could result in enhanced vitamin D metabolism, which would explain persistently low vitamin D level despite replacement with such high doses. The significant improvement in his symptoms with supplementation resulting in increased mobility despite not having a normal vitamin D level suggest other pleiotropic effects of vitamin D on muscle and bone as well. Additionally effects of liver transplantation on vitamin D metabolism need to be explored further.

Paget ‘s Disease: Not So Typical for Atypical Femur Fracture

Introduction: Atypical femur fractures (AFF) are reported in patients taking prolonged bisphosphonate therapy, but Paget’s disease (PD) has been rarely reported as a cause of AFF. Case: 71-year-old female with past medical history of right hip osteoarthritis, seizure disorder, hypertension, and Hashimoto’s thyroiditis presented with persistent right hip pain. There was no history of trauma or fall. She had otosclerosis with bilateral hearing loss and bilateral stapedectomies. Her medications were primidone, levothyroxine, lisinopril-hydrochlorothiazide, and vitamin D. She did not smoke tobacco or drink alcohol. She had elevated serum alkaline phosphatase of 300 U/L (35–104). The X-ray of the skull was negative for any cortical thickening. CT of right femur revealed cortical thickening and coarsening of trabeculae of the proximal right femur consistent with PD and incomplete atypical subtrochanteric proximal fracture. Urine NTx 303 BCE/mM Cr (<89). Bone scan showed uptake in the R proximal femur, L distal tibia, and L3-L4 vertebral bodies suspicious of PD. DXA showed osteopenia. She was given zoledronic acid 5 mg IV. Discussion: PD leads to an increased incidence of fractures particularly of the lower extremities with most fractures transverse in nature. Non-union is not uncommon1. Stress fractures in PD are caused by disorganized bone remodeling due to excessive breakdown and formation of bone. Our patient met the major criteria for AFF as per the ASBMR 2010 task force report but there was no exposure to bisphosphonates2. The ASBMR task force recommended that bisphosphonates should be discontinued in patients with bisphosphonate-associated AFF due to their severely suppressed bone turnover status. On the other hand, the AFF in patients with PD may heal in response to bisphosphonate treatment.

A Case of Chronic Bone Pain in Mc-CuneAlbright Syndrome

Introduction: McCune-Albright syndrome (MAS) is a rare genetic disorder that effects the endocrine, skin and bone systems and caused by a somatic mutation in the G protein activating adenylyl cyclase resulting in abnormal osteoblast differentiation and development of fibrous dysplasia (FD). We describe a patient with extensive fibrous dysplasia and severe bone pain in the setting of MAS. Case: A 56-year-old female with a history of MAS was evaluated in the osteoporosis clinic for chronic bone pain. She was diagnosed with MAS at the age of two when she presented with precocious puberty and treated with hormonal blockade. She had multiple orthopedic issues including chronic left hip and lower back pain with impending fracture and pelvic microfractures treated with prophylactic rodding and cement osteoplasty at age 46 and 51 respectively. She was taking Tramadol as needed. The patient reported an inch of height loss, and imaging revealed T4 compression fracture. She was treated with zoledronic acid 4 mg IV on a monthly basis for 1 year without any improvement in bone density or pain symptoms She reached menarche at age 12, and is currently menopausal. Her calcium intake was limited but vitamin D intake was adequate. The patient was quite active performing intense cardio exercises several times a week. Physical exam was remarkable for café-au-lait spots on her left trunk and abdomen not crossing the mid-line. Bone density showed spine DJD, right femoral neck and forearm T scores of -1.1 and -1.6 respectively. Recent CT scan demonstrated multiple lucent lesions in the thoracic spine, bilateral ribs and sternum consistent with fibrous dysplasia. Biochemical evaluation showed high bone turnover; urine NTX of 74 nM BCE/mM creatinine (26–124 nM BCE/mM) and bone specific alkaline phosphatase 80.7 U/L (14.2–42.7) Calcium and vitamin D levels were within limits. The patient initiated denosumab 60mg every 6 months to determine if significant reduction in bone turnover and bone pain would follow. Discussion: As patients with MAS and FD have elevated RANKL levels and increased bone resorption, treatments that reduce bone turnover markers (BTMs) have been studied. Bisphosphonates have demonstrated decline in BTMs but with mixed results regarding improvement of clinical symptoms (1). In a recent study, denosumab, a monoclonal antibody to RANK-L was given at either 3- or 6-month intervals. Patients who received 3-month interval injections demonstrated a sustained suppression of BTM and improvement of pain (2). Thus, denosumab is a promising and well-tolerated agent that may be effective in FD, especially when response to bisphosphonates is inadequate.

Prolonged Hypocalcemia After a Single Dose of Denosumab in Chronic Kidney Disease

Introduction: Denosumab, a monoclonal antibody that inhibits RANK L (receptor activator nuclear factor-kappa beta ligand), is one of the few medications that can be used to treat osteoporosis in patients with chronic kidney disease (CKD). However, its use is associated with a much higher incidence of hypocalcemia in this patient population. What remains unclear is the duration of hypocalcemia after denosumab use. We describe a case of prolonged hypocalcemia of 9 months in a patient with CKD after a single dose of denosumab. Case: A 64-year-old Caucasian man with a history of bilateral lung transplant for interstitial pulmonary fibrosis and CKD Stage IV was referred to the Endocrinology clinic for evaluation of steroid-induced osteoporosis. Bone density scan was consistent with osteoporosis with the lowest T-score of -2.8 at the left femoral neck, which showed a 25.3% decline from a previous one two years prior. His labs upon initial visit: 25 hydroxy Vitamin D: 36.5 ng/mL (30–100), 1, 25 hydroxy vitamin D 32 pg/ml (19.9–79.3), corrected Serum Calcium 8.9 mg/dL (8.5–10.5), Serum Cr 4.38 mg/dL (0.6–1.4), PTH 157 pg/mL (10–65), Serum Alkaline Phosphatase 61 Units/L (25–125), Urine NTX 39 nM BCE/mM creatinine (21–83). After discussing risks and benefits, he was given a dose of subcutaneous denosumab 60 mg. He had been started on Calcium/Vitamin D (600 mg/400 IU BID) prior to receiving his dose. Keeping in mind the increased risk of hypocalcemia given his history of CKD, his corrected serum calcium was checked one week later, and it was 6.5 mg/dL. The patient was asymptomatic. However, given the severity of his hypocalcemia, he was started on calcitriol 0.25 mcg oral BID and calcium carbonate 1200 mg daily. He did show mild improvement in three days to a corrected calcium of 7.0 mg/dL. His calcitriol was briefly increased to 0.5 mcg BID and calcium carbonate was increased to 1800 mg daily. The regimen was weaned to calcitriol 0.25 mcg daily and previous calcium/Vitamin D dosing later that month. Thereafter, his labs were monitored regularly and there were several unsuccessful attempts made to decrease the calcitriol/calcium carbonate. Given persistent hypocalcemia, other bloodwork including a bone specific alkaline phosphatase and celiac screen were checked which were unremarkable. Finally, nine months after his denosumab dose, calcitriol was discontinued safely. Serum calcium levels have remained stable thereafter. Given prolonged hypocalcemia, it was decided not to administer another dose of denosumab. Conclusion: Patients with CKD who receive denosumab are not only at risk for developing severe, but also prolonged hypocalcemia. Therefore, it is imperative to monitor serum calcium levels, not only immediately after receiving a dose, but serially.

Lipocalin 2 serum levels correlate with age and bone turnover biomarkers in healthy subjects but not in postmenopausal osteoporotic women

PurposeLipocalin 2 (LCN2) is an adipokine involved in many physiological functions, including bone metabolism. We previously demonstrated its implication in mouse models of mechanical unloading-induced osteoporosis and in a cohort of bed rest volunteers. We therefore aimed at studying its involvement in postmenopausal osteoporosis. MethodsWe measured serum LCN2 and correlated its levels to Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1), Tartrate Resistant Acid Phosphatase 5B (TRAcP5B), sclerostin, urinary N-terminal telopeptide of type I collagen (NTX), serum C-terminal telopeptide of type I collagen (CTX), parathyroid hormone and vitamin K by ELISA performed in a cohort of younger (50–65 years) and older (66–90 years) osteoporotic women in comparison to healthy subjects. A cohort of male healthy and osteoarthritic patients was also included. Sobel mediation analysis was used to test indirect associations among age, LCN2 and DKK1 or NTX. ResultsLCN2 levels were unchanged in osteoporotic and in osteoarthritis patients when compared to healthy subjects and did not correlate with BMD. However, serum LCN2 correlated with age in healthy women (R = 0.44; P = 0.003) and men (R = 0.5; P = 0.001) and serum concentrations of DKK1 (R = 0.47; P = 0.003) and urinary NTX (R = 0.34; P = 0.04). Sobel mediation analysis showed that LCN2 mediates an indirect relationship between age and DKK1 (P = 0.02), but not with NTX, in healthy subjects. ConclusionsTaken together, the results suggest a hitherto unknown association between LCN2, DKK1 and age in healthy individuals, but not in postmenopausal osteoporotic women.

Effect of selenium supplementation on musculoskeletal health in older women: a randomised, double-blind, placebo-controlled trial

SummaryBackgroundObservational and preclinical studies show associations between selenium status, bone health, and physical function. Most adults in Europe have serum selenium below the optimum range. We hypothesised that selenium supplementation could reduce pro-resorptive actions of reactive oxygen species on osteoclasts and improve physical function.MethodsWe completed a 6-month randomised, double-blind, placebo-controlled trial. We recruited postmenopausal women older than 55 years with osteopenia or osteoporosis at the Northern General Hospital, Sheffield, UK. Participants were randomly assigned 1:1:1 to receive selenite 200 μg, 50 μg, or placebo orally once per day. Medication was supplied to the site blinded and numbered by a block randomisation sequence with a block size of 18, and participants were allocated medication in numerical order. All participants and study team were masked to treatment allocation. The primary endpoint was urine N-terminal cross-linking telopeptide of type I collagen (NTx, expressed as ratio to creatinine) at 26 weeks. Analysis included all randomly assigned participants who completed follow-up. Groups were compared with analysis of covariance with Hochberg testing. Secondary endpoints were other biochemical markers of bone turnover, bone mineral density, short physical performance battery, and grip strength. Mechanistic endpoints were glutathione peroxidase, highly sensitive C-reactive protein, and interleukin-6. This trial is registered with EU clinical trials, EudraCT 2016-002964-15, and ClinicalTrials.gov, NCT02832648, and is complete.Findings120 participants were recruited between Jan 23, 2017, and April 11, 2018, and randomly assigned to selenite 200 μg, 50 μg, or placebo (n=40 per group). 115 (96%) of 120 participants completed follow-up and were included in the primary analysis (200 μg [n=39], 50 μg [n=39], placebo [n=37]). Median follow-up was 25·0 weeks (IQR 24·7–26·0). In the 200 μg group, mean serum selenium increased from 78·8 (95% CI 73·5–84·2) to 105·7 μg/L (99·5–111·9). Urine NTx to creatinine ratio (nmol bone collagen equivalent:mmol creatinine) did not differ significantly between treatment groups at 26 weeks: 40·5 (95% CI 34·9–47·0) for placebo, 43·4 (37·4–50·5) for 50 μg, and 42·2 (37·5–47·6) for 200 μg. None of the secondary or mechanistic endpoint measurements differed between treatment groups at 26 weeks. Seven (6%) of 120 participants were withdrawn from treatment at week 13 due to abnormal thyroid-stimulating hormone concentrations (one in the 200 μg group, three in the 50 μg group, and three in the placebo group) and abnormal blood glucose (one in the 50 μg group). There were three serious adverse events: a non-ST elevation myocardial infarction at week 18 (in the 50 μg group), a diagnosis of bowel cancer after routine population screening at week 2 (in the placebo group), and a pulmonary embolus due to metastatic bowel cancer at week 4 (in the 200 μg group). All severe adverse events were judged by the principal investigator as unrelated to trial medication.InterpretationSelenium supplementation at these doses does not affect musculoskeletal health in postmenopausal women.FundingUK National Institute for Health Research Efficacy and Mechanism Evaluation programme.

Testing the Functional Model of Bone Development: Direct and Mediating Role of Muscle Strength on Bone Properties in Growing Youth.

This study examines the functional model of bone development in peri-pubertal boys and girls. Specifically, we implemented a mixed-longitudinal design and hierarchical structural models to provide experimental evidence in support of the conceptual functional model of bone development, postulating that the primary mechanical stimulus of bone strength development is muscle force. To this end, we measured radial and tibial bone properties (speed of sound, SOS), isometric grip and knee extensors strength, bone resorption (urinary NTX concentration), body mass index (BMI), somatic maturity (years from peak height velocity) and skeletal maturity (bone age) in 180 children aged 8–16 years. Measurements were repeated 2–4 times over a period of 3 years. The multilevel structural equation modeling of 406 participant-session observations revealed similar results for radial and tibial SOS. Muscle strength (i.e., grip strength for the radial and knee extension for tibial model) and NTX have a significant direct effect on bone SOS (β = 0.29 and −0.18, respectively). Somatic maturity had a direct impact on muscle strength (β = 0.24) and both a direct and indirect effect on bone SOS (total effect, β = 0.30). Physical activity and BMI also had a significant direct impact on bone properties, (β = 0.06 and −0.18, respectively), and an additional significant indirect effect through muscle strength (β = 0.01 and 0.05, respectively) with small differences per bone site and sex. Muscle strength fully mediated the impact of bone age (β = 0.14) while there was no significant effect of energy intake on either muscle strength or bone SOS. In conclusion, our results support the functional model of bone development in that muscle strength and bone metabolism directly affect bone development while the contribution of maturity, physical activity, and other modulators such as BMI, on bone development is additionally modulated through their effect on muscle strength.

Retraction Note to: Effect of alendronate on bone mineral density and bone turnovermarkers in post-gastrectomy osteoporotic patients.

Alendronate decreases the urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX; about 45% at 3 months) and serum levels of alkaline phosphatase (ALP; about 27% at 24 months), leading to an increase in lumbar spine bone mineral density (BMD; about 9% at 24 months) in postmenopausal Japanese women with osteoporosis. However, the effectiveness of oral bisphosphonates on osteoporosis remains to be established in patients who have undergone a gastrectomy. The objective of the present case series study was to examine the effect of alendronate on BMD and bone turnover markers in post-gastrectomy osteoporotic patients. Sixteen patients (3 men and 13 postmenopausal women) with osteoporosis, who had undergone a gastrectomy (mean age: 69.1 years), were recruited in our outpatient clinic. All the patients were treated with alendronate (5 mg daily or 35 mg weekly) for 24 months. The effects of alendronate on lumbar spine (women) or total hip (men) BMD and urinary NTX and serum ALP levels were examined. A total or partial gastrectomy had been performed for eight patients each. The mean duration after surgery was 16.0 years. With alendronate therapy, urinary NTX levels significantly decreased at 3 months (−27.0%). Serum ALP levels decreased (−12.1%) and lumbar spine BMD increased (+5.2%), but total hip BMD did not significantly change (+0.6%) at 24 months. No severe adverse events were observed, and alendronate therapy was well tolerated. These results suggest that alendronate mildly increases lumbar spine BMD by mildly reducing bone turnover in osteoporotic patients after a gastrectomy.

Bisphosphonates for the treatment of fibrous dysplasia of bone

Fibrous dysplasia of bone (FD) is a rare congenital bone disease, due to a somatic mutation of GNAS. This mutation results in a defect of osteoblast differentiation and mineralization and also an increase in bone resorption by large active osteoclasts. Bone pain is present in half of patients and is the main determinant of quality of life of patients with FD. Bisphosphonates are known to reduce bone pain and reduce the risk of fracture in patients with bone metastases or Paget's disease. Bisphosphonates may have similar effects in FD. In this article, we have reviewed the therapeutic potential of bisphosphonates to reduce bone pain due to FD, improve bone strength and reduce the occurrence of fracture. We have reviewed 234 articles examining the effect of bisphosphonates on FD/McCune Albright Syndrome with no date limit, in PubMed and selected the articles with highest quality of methodology. Pamidronate therapy significantly decreased bone pain and bone resorption (urinary NTX, urinary and serum CTX). Pamidronate may improve radiological lesions of FD patients (filling of osteolytic lesion and/or cortical thickening). This data with intravenous pamidronate, however, has been obtained from observational studies and no randomized controlled trial is available. Randomized placebo-controlled trials of oral bisphosphonates (alendronate or risedronate) have failed to demonstrate a significant decrease in bone pain over placebo. Several studies including one randomized controlled trial have shown an increase in bone mineral density (BMD) at FD sites with oral and intravenous bisphosphonate treatment. No effect on occurrence of fracture has been reported. In conclusion, intravenous bisphosphonates may be proposed to treat persistent, moderate to severe bone pain of FD, e.g., according to the guidelines from the FD/MAS International Consortium. Oral bisphosphonates should not be used in this indication.