Nonalcoholic fatty liver disease (NAFLD) is associated with type 2 diabetes (T2D) and vice versa, and both conditions are associated with an increased risk of fractures and altered bone turnover. Although patients with NAFLD typically suffer from decreased bone mineral density (BMD), T2D is associated with normal to high BMD. The pathophysiology is uncertain but may involve the gut-bone axis.

We investigated the influence of the gut on glucose-induced changes in plasma bone turnover markers in healthy controls and patients with T2D and/or biopsy-verified NAFLD.

Cross-sectional cohort study.

Patients with NAFLD with normal glucose tolerance, patients with NAFLD and T2D, patients with T2D without liver disease, and healthy controls.

Four-hour 50-g oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion (IIGI).

Collagen type 1 C-telopeptide (CTX), osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), and parathyroid hormone.

Plasma glucose levels achieved during OGTTs were successfully matched on corresponding IIGI days. Patients with NAFLD and T2D exhibited similar CTX suppression during the two glucose challenges (P = 0.46) and pronounced suppression of P1NP during IIGI compared with OGTT. Conversely, remaining groups showed greater (P < 0.05) CTX suppression during OGTT and similar suppression of bone formation markers during IIGI and OGTT.

OGTT-induced CTX suppression seems to be impaired in patients with NAFLD and T2D, but preserved in patients with either NAFLD or T2D, suggesting that coexistence of T2D and NAFLD may affect gut-bone axis.

OBJECTIVE

Disordered eating may negatively impact bone in athletes. However, it is not known whether this effect is independent of the associated amenorrhea and relative hypercortisolemia. We aimed to compare attitudes, feelings, and cognitions associated with disordered eating using the Three-Factor Eating Questionnaire (TFEQ) and Eating Disorder Inventory-2 (EDI-2) in normal-weight oligomenorrheic athletes (OA), eumenorrheic athletes (EA), and nonathletes, and determine the associations with bone independent of confounders.

METHODS

109 OA, 39 EA, and 36 nonathletes (14-25 years) completed the TFEQ and EDI-2. Dual-energy X-ray absorptiometry was used to assess spine bone mineral density (BMD), and high-resolution pQCT to assess radius microarchitecture. We measured integrated cortisol (q 20', 11 PM-7 AM), bone formation (procollagen Type 1 N-terminal propeptide, P1NP), and resorption (C-telopeptide, CTX) markers in a subset.

RESULTS

OA had lower spine BMD Z-scores than EA. Cognitive eating restraint (CER), drive for thinness (DT), ineffectiveness, and interoceptive awareness (IA) were higher in OA than EA (p < 0.05); CER was higher in OA versus nonathletes (p = 0.03). Pulsatile cortisol was positively associated with DT, ineffectiveness, and IA (p < 0.03). CER was inversely associated with BMD Z-scores and P1NP, and ineffectiveness with radius cross-sectional area even after controlling for age, BMI, amenorrhea duration, and cortisol (p < 0.03).

CONCLUSIONS

Higher CER in athletes independently predicts lower BMD.

In observational studies, vitamin D deficiency is a risk factor for low bone density and future fractures, whereas a causal relation has been difficult to show in randomized controlled trials (RCTs). Similarly, vitamin D deficiency has been associated with increased bone turnover, but RCTs with vitamin D have not shown conclusive effects. This could be due to inclusion of vitamin D sufficient subjects and low vitamin D doses. In the present study 399 subjects with mean baseline serum 25-hydroxyvitamin D (25(OH)D) 34.0 nmol/L completed a four months intervention with vitamin D₃ 20,000 IU per week versus placebo. Mean serum 25(OH)D increased to 89.0 nmol/L in the vitamin D group and decreased slightly in the placebo group. A small, but significant, decrease in the bone formation marker procollagen of type 1 amino-terminal propeptide (P1NP) was seen in the vitamin D group as compared to the placebo group (mean delta P1NP -1.2 pg/mL and 1.5 ng/mL, respectively, P < 0.01). No significant effects were seen on serum carboxyl-terminal telopeptide of type 1 collagen (CTX-1), Dickkopf-1, sclerostin, tumor necrosis factor-alpha, osteoprotegerin, receptor activator of nuclear factor ĸB ligand, or leptin. Subgroup analyses on subjects with low baseline serum 25(OH)D did not yield additional, significant results. In subjects with high baseline serum parathyroid hormone (PTH) > 6.5 pmol/L and post-intervention decrease in PTH, the decrease in P1NP was more pronounced, they also exhibited significantly reduced serum CTX-1 and increased serum sclerostin. In conclusion, supplementation with vitamin D appears to suppress bone turnover, possibly mediated by PTH reduction. Our findings need to be confirmed in even larger cohorts with vitamin D insufficient subjects.

Bone metabolic markers consist of bone formation markers, which are secreted from osteoblasts (BAP, OC, P1CP, P1NP) , and bone resorption markers, which are metabolites of bone type 1 collagen or secreted from osteoclasts (PYD, DPD, NTX, CTX, 1CTP, TRACP) . Those bone metabolic markers are useful for : (1) diagnosis of bone metastases, (2) follow-up during treatment of bone metastases, and (3)predicting prognosis of bone metastases.

The purpose of this study was to evaluate the influence of gamma-glutamyl transferase (GGCX) gene polymorphisms on the response of serum undercarboxylated osteocalcin (ucOC) and bone turnover markers 3 months after treatment with menatetrenone. One hundred and forty postmenopausal Thai women were enrolled and assigned to receive 45 mg/day treatment of menatetrenone (MK-4) concurrently with calcium 1.2 g and vitamin D 400 IU for 3 months. Demographic characteristics, GGCX genotyping, serum bone turnover markers and ucOC levels were obtained from all participants at baseline. We evaluated the reduction of ucOC at 3 months and the reduction of beta-CTx and P1NP at 1 and 3 months. The responses were compared between the different genotypes of GG and GA + AA groups. There was a significant reduction of serum ucOC, beta-CTx and P1NP from the baseline at 3 months (p < 0.001) though there was no significant difference between genotypes (GG vs. GA + AA; p>> 0.05). Nonetheless, a subgroup analysis of postmenopausal women who 65 years of age or over (N = 37) revealed a significant difference between the two groups in the reduction of ucOC. Menatetrenone significantly reduced serum ucOC as well as beta-CTX and P1NP from the baseline. GGCX polymorphism appeared to have an influence over the reduction of ucOC especially in older women (age ≥65). Furthermore, the groups which have "A" allele trend to being more efficient in reducing the serum ucOC level than the group which does not have it.

We examined the efficacy and safety of denosumab as treatment for glucocorticoid-induced osteoporosis (GIOP) patients complicated with rheumatic diseases, by measuring patients' lumber bone mineral density (BMD) and bone turnover markers. A total of 66 consecutive patients for whom denosumab was initiated between July 2013 and August 2016 were enrolled and evaluated for 12 months. All of the patients were treated with glucocorticoids for underlying rheumatic diseases. The clinical assessment included measurements of the BMD of the lumbar spine (L2-L4) by a dual-energy X-ray absorptiometry technique and the bone turnover markers N-terminal telopeptide of type 1 collagen (NTX) in urine, serum intact procollagen type 1 N-terminal propeptide (P1NP), and bone-specific alkaline phosphatase (BAP) at baseline, 6 months and 12 months after the start of denosumab treatment. Adverse events (AEs) until 12 months were also analyzed. The mean percentage changes in BMD from baseline to 6 and 12 months were significant (2.85% increase, p < 0.0001 and 4.40% increase, p < 0.0001, respectively) regardless of the prior anti-osteoporotic drugs treatment (16 no transition from anti-osteoporotic drugs, 27 transition from bisphosphonate, 23 transition from teriparatide). The decreases in NTX, P1NP and BAP at 6 and 12 months were also significant. No serious AEs were noted. A multivariable logistic analysis showed that the prednisolone dose at baseline was associated with the clinical response to denosumab. In a real-world setting, denosumab was effective and safe for treating GIOP patients complicated with rheumatic diseases regardless of prior anti-osteoporotic drug treatment.

OBJECTIVE

The study was carried out to evaluate safety and efficacy of once-a-week medication of Kasparalendronate for inhibiting high bone turnover rate.

METHODS

Forty-nine postmenopausal osteoporotic participants were included in the study. This investigation was carried out as an open study. The participants received the drug every weekfor 12 weeks. Pain, drugside effects and bone turnover markers were evaluated at the 6"' week and 12' week after the first visit.

RESULTS

None had significant complication and all could complete the trial. Thirteen participants, (26.3%), had minimal side ffects, which the trial drug could be administered until the end ofstudy. At the 12th week follow-up, 42/49 participants (85.7%) had normal serum Beta-crosslab and 45/49 participants (91.8%) had normal serum N-MID osteocalcin. None showed any decrease in serum P1NP All participants had slight reduction in serum alkaline phosphatase.

CONCLUSIONS

The trial drug could inhibit high bone turnover in about 85% of post-menopausalparticipants within 12 weeks of drug administration and no severe side effect took place.

BACKGROUND

Patients receiving postoperative radioiodine therapy for advanced differentiated thyroid carcinoma (DTC) are repeatedly in short-term thyroid hormone deficiency, whose bone turnover state is not fully understood.

METHODS

Serum bone turnover markers (BTMs), bone specific alkaline phosphatase (BALP), type 1 procollagen N-terminal propeptide (P1NP), osteocalcin (OC), and the beta-isomerized C-terminal telopeptide of type 1 collagen (beta-CTx) were measured in 50 adult male DTC patients after 4-week suspension of levothyroxine replacement therapy and 40 matched euthyroid controls. Relationships between parameters of thyroid function (free triiodothyronine, FT3; free thyroxine, FT4; thyroid stimulating hormone, TSH) and the BTMs were studied.

RESULTS

The patients had significantly decreased OC (-37.6%, P<0.001) and beta-CTx (-35.5%, P<0.001) compared with the controls, showing FT3 as the independent risk factor for OC (R2=0.425, P<0.001) and beta-CTx (R2=0.124, P<0.001). Partial correlation analysis showed that only FT3 was significantly correlated with OC after controlling FT4 and TSH (r=0.362, P=0.001).

CONCLUSIONS

DTC patients have moderately decreased bone turnover after short-term suspension of thyroxine suppressive therapy, with serum FT3 concentration as the predominant and independent risk factor.

OBJECTIVE

Gaucher disease is an inherited disorder caused by deficit of acid β-glucocerebrosidase, responsible for the degradation of glucosylceramide to ceramide and glucose. Although the disorder is primarily hematologic, bone is the second most commonly affected structure. Cathepsin K (CATK) is an enzyme involved in bone remodelling process. It has been proposed that determination of its serum concentrations may provide additional information to other biomarkers.

METHODS

The study included 20 control subjects and 20 Gaucher type 1 patients from Andalusia and Extremadura regions. We analyzed the biomarkers of bone remodelling: the bone alkaline phosphatase (B-ALP), the N-terminal propeptide of type 1 procollagen (P1NP), the β carboxyterminal telopeptide of type 1 collagen (CTx) and the CATK through electrochemiluminescence and immunoassay techniques.

RESULTS

There is an increase in levels of CATK, CATK/P1NP and CATK/B-ALP ratios in type 1 Gaucher patients compared to the control group. Considering the existence of skeletal manifestations in the patient group, the CATK and CATK/P1NP ratio showed higher levels in patients with bone damage compared to those without it.

CONCLUSIONS

Although imaging studies are the gold standard for monitoring bone disease in type 1 Gaucher patients, the utility of CATK should be considered as a possible indicator of bone damage in these patients. Furthermore, this parameter can be used in the monitoring of the treatment of bone pathology.

Our goal was to determine if venlafaxine has a negative effect on bone metabolism. Rats were divided into three groups. The sham-operated control group (SHAM), the control group after orchidectomy (ORX), and the experimental group after orchidectomy received venlafaxine (VEN ORX) in standard laboratory diet (SLD) for 12 weeks. Bone mineral content (BMC) was measured by dual energy X-ray absorptiometry (DXA). Bone marker concentrations of carboxy-terminal cross-linking telopeptide of type I collagen (CTX-I), osteoprotegerin (OPG), amino-terminal propeptide of procollagen type I (P1NP), bone alkaline phosphatase (BALP), sclerostin and bone morphogenetic protein 2 (BMP-2) were examined in bone homogenate. The femurs were used for biomechanical testing. Compared to the ORX group we found lower BMD in the diaphysis area of the femur in the VEN ORX group, suggesting a preferential effect on cortical bone. Of the bone metabolism markers, there was significant decrease (ORX control group versus VEN ORX experimental group) in BALP levels and increase in sclerostin and CTX-I levels, suggesting a decrease in osteoid synthesis and increased bone resorption. The results suggest that the prolonged use of venlafaxine may have a negative effect on bone metabolism. Further studies are warranted to establish whether venlafaxine may have a clinically significant adverse effect on bone.

BACKGROUND

Vitamin D status is not evaluated routinely in cancer patients with bone metastasis who are treated with bisphosphonates.

OBJECTIVE

To assess the effect of vitamin D status on risk of hypocalcemia and quality of life in these patients.

METHODS

We performed laboratory tests for routine serum biochemistry, 25(OH)D, plasma parathyroid hormone (PTH) and bone turnover markers (CTX, P1NP) in 54 patients aged 57.5 +/- 13 years treated with intravenous bisphosphonates.

RESULTS

Most of the patients (n = 44, 77.8%) did not receive calcium and vitamin D supplementation. Their mean serum 25(OH)D levels (12.83 +/- 6.86 ng/ml) correlated with vitamin D daily intake (P = 0.002). In 53 patients (98.1%) 25(OH) D levels were suboptimal (< 30 ng/ml). Albumin-corrected calcium levels correlated with plasma PTH (P = 0.001). No correlation was observed between daily calcium intake and serum calcium (P = 0.45). Hypocalcemia was observed in one patient. Mean plasma PTH was 88.5 - 65 ng/L. Plasma PTH correlated negatively with 25(OH)D serum levels (P = 0.003) and positively with P1NP (P = 0.004). Albumin-corrected calcium correlated negatively with P1NP (mean 126.9 +/- 191 ng/ml) but not with CTX levels (mean 0.265 +/- 0.1 ng/ml) (P < 0.001). There was no correlation among quality of life parameters, yearly sun exposure and 25(OH)D levels (P = 0.99).

CONCLUSIONS

Vitamin D deficiency is frequent in oncology patients with bone metastasis treated with bisphosphonates and might increase bone damage. Our results indicate a minor risk for the development of severe hypocalcemia in vitamin D-deficient patients receiving bisphosphonate therapy. Although vitamin D deficiency might have some effect on the quality of life in these patients, it was not proven significant.

Context: Interleukin 6 (IL-6) contributes to bone remodeling in preclinical studies. Clinical trials investigating the role of IL-6 in bone remodeling are limited.

Objective: To investigate if IL-6 regulates bone remodeling in humans.

Design: Plasma concentrations of the bone resorption marker carboxy-terminal type I collagen crosslinks (CTX) and of the bone formation marker procollagen type 1 N-terminal propeptide (P1NP) were measured during a mixed-meal tolerance test (MMTT) in 3 placebo-controlled human studies.

Participants: Five healthy individuals participated in study 1; 52 obese individuals, in study 2; and 10 healthy individuals, in study 3.

Interventions: Study 1 was a single-blinded crossover study consisting of a 1-h infusion of saline (placebo) or the IL-6 receptor antibody tocilizumab followed by an exercise bout. Study 2 was a randomized, double-blinded 12-week exercise training intervention study. Participants received infusions of saline or tocilizumab. Study 3 was a randomized, double-blinded, crossover study consisting of 30 min infusion of saline or IL-6.

Main outcomes measures: Effect of IL-6 on CTX levels.

Results: CTX was significantly (P < 0.01) decreased during MMTTs in all 3 studies. Treatment with tocilizumab did not affect exercise or meal induced changes in plasma CTX or P1NP concentrations acutely (study 1) or after a 12-week treatment period (study 2). Exogenous IL-6 had no effect on CTX or P1NP plasma concentrations (study 3).

Conclusions: IL-6 may not regulate bone remodeling in humans.

Keywords: bone formation; bone resorption; interleukin-6.

End-stage renal disease is associated with mineral and bone disorders. Guidelines recommending therapies should be based on serial assessments of biomarkers, and thus on variations (Δ), rather than scattered values. We analyzed the correlations between ΔPTH and Δbone biomarkers such as bone-specific alkaline phosphatase (b-ALP), Beta-CrossLaps (CTX), osteocalcin, intact serum procollagen type-1 N-propeptide (P1NP), and tartrate-resistant acid phosphatase 5B (TRAP-5B) at different time-points. In this prospective observational analysis, variations of biomarkers were followed after 6-week (n = 129), 6-month (n = 108) and one-year (n = 93) period. Associations between variations were studied by univariate linear regression. Patients followed for one-year period were classified (increaser or decliner) according to variations reaching the critical difference. Over the 6-week period, only ΔCTX was correlated with ΔPTH (r = 0.38, p < 0.0001). Over the one-year period, correlations between ΔPTH and Δbone biomarkers became significant (r from 0.23 to 0.47, p < 0.01), except with ΔTRAP-5b. Correlations between Δbone biomarkers were all significant after one-year period (r from 0.31 to 0.68, p < 0.01), except between Δb-ALP and ΔTRAP-5b. In the head-to-head classifications (decliners/increasers), the percentage of concordant patients was significantly higher over the one-year than the 6-week period. A concordance between ΔPTH and Δbone biomarkers is observed in dialysis patients, but only after a long follow-up.

Mineralocorticoid receptor (MR) antagonism may affect bone turnover via direct and indirect pathways involving parathyroid hormone, but randomized controlled trials are lacking. In a pre-specified analysis of the "Eplerenone in primary hyperparathyroidism" placebo-controlled, randomized trial (ISRCTN 33941607), effects of eight weeks MR-blockade with eplerenone on bone turnover markers in 97 patients with primary hyperparathyroidism were tested. Mean age was 67.5±9.5years, and 76 (78.4%) were females. In analysis of covariance with adjustment for baseline values, eplerenone had no significant effect on isoform 5b of the tartrate-resistant acid phosphatase (TRAP), beta-crosslaps, N-terminal propeptide of procollagen type 1 (P1NP), osteocalcin and bone-specific alkaline phosphatase. There was no significant cross-sectional correlation between plasma aldosterone concentration or the aldosterone-to-renin ratio and markers of bone turnover in multivariate linear regression models at baseline. These data provide first evidence from a randomized and placebo-controlled trial that short-term MR antagonism may not affect bone turnover, at least in patients with primary hyperparathyroidism.

In women, age-related bone loss is associated with increased risk of bone fracture. Existing therapies are associated with severe side effects; thus, there is a need to find alternative medicines with less or optimal side effects. Cissus quadrangularis (CQ), an Ayurvedic medicine used to enhance fracture healing, was tested for its bone protective properties and studied to discern the mechanism by which it is beneficial to bone. Female Sprague Dawley rats were either sham operated or ovariectomized and were fed CQ for 3 months. Several biochemical markers, cytokines and hormones were assayed. Femur, tibia and lumbar vertebrae were subjected to pQCT and µCT densitometry. MC3T3 cells were cultured, treated with CQ and used to analyze miRNA content and subjected to qPCR for gene expression analysis related to bone metabolism. CQO rats showed protected bone mass and microarchitecture of trabecular bone in the distal femoral metaphysis and the proximal tibial metaphysis. The lumbar vertebrae, however, showed no significant changes. Serum protein expression levels of P1NP increased and Trap5b and CTX levels decreased with in vivo CQ treatment. Some influence on the anti- and pro-inflammatory markers was also observed. Significantly high level of estradiol in the CQO rats was observed. In vitro expression of a few genes related to bone metabolism showed that osteocalcin increased significantly. The other genes-collagen I expression, SPP1, BMP2, DCAT1-decreased significantly. Certain miRNA that regulate bone turnover using the BMP pathway and Wnt signaling pathways were upregulated by CQ. qPCR after acute treatment with CQ showed significantly increased levels of osteocalcin and decreased levels of Wnt/β catenin antagonist DCAT1. Overall, CQ protected the microarchitecture of the long bones from ovariectomy-induced bone loss. This may be because of decreased inflammation and modulation through the BMP and Wnt signaling pathways. We conclude that CQ is a potential therapeutic agent to treat postmenopausal osteoporosis with no side effects.

BACKGROUND

Sclerostin has been directly related to bone turnover increase in dietary-induced weight loss in non-diabetics. This has not been studied in type 2 diabetes, a condition characterized by increased circulating sclerostin and impaired bone turnover.

OBJECTIVE

To study the effect of dietary weight loss and quality of the dietary intervention on changes of sclerostin and bone turnover markers in type 2 diabetes.

METHODS

This was a post-hoc analysis of the MADIAB trial, a 21-day randomized controlled trial on overweight/obese type 2 diabetes patients. Patients were randomly assigned 1:1 to the Ma-Pi2 macrobiotic diet or a control diet based on dietary guidelines for type 2 diabetes. Serum sclerostin and circulating markers of bone resorption and formation (P1NP) were measured by enzyme linked immunosorbent assay in 40 subjects (1:1) at baseline and after 21 days treatment.

RESULTS

Both Ma-Pi2 and the control diet groups had significant decreases in body weight (6.0 ± 0.2 vs. 3.2 ± 0.1 %, p < 0.001). Sclerostin increased significantly in the two groups (all p < 0.001) but Ma-Pi2 diet group experienced a greater increase in sclerostin (34.5 vs. 15 %; p = 0.024). Serum circulating markers of bone resorption increased in the two groups (all p < 0.001); circulating markers of bone resorption at the end of the treatment tended to be higher in Ma-Pi2 diet than the control diet group (p = 0.06). P1NP did not change significantly in the two group compared to baseline. Sclerostin changes were related to body mass index reduction (r = -0.37; p = 0.02).

CONCLUSIONS

Diet-induced weight loss may induce significant and rapid changes in bone turnover and sclerostin levels. These changes may further impair bone health in subjects with type 2 diabetes.

Obesity and impaired lipid metabolism increase circulating and local fatty acid (FA) levels. Our previous studies showed that a high high-saturated -fat diet induced greater bone loss in mice than a high high-unsaturated-fat diet due to increased osteoclast numbers and activity. The impact of elevated FA levels on osteoblasts is not yet clear. We induced obesity in 4 week old male mice using a palmitic acid (PA)- or oleic acid (OA)-enriched high fat high-fat diet (HFD) (20 % of calories from FA), and compared them to mice on a normal (R) caloric diet (10 % of calories from FA). We collected serum to determine FA and bone metabolism marker levels. Primary osteoblasts were isolated; cultured in PA, OA, or control (C) medium; and assessed for mineralization activity, gene expression, and ceramide levels. Obese animals in the PA and OA groups had significantly lower serum levels of bone formation markers P1NP and OC compared to normal weight animals (*p < 0.001), with the lowest marker levels in animals on an PA-enriched HFD (*p < 0.001). Accordingly, elevated levels of PA significantly reduced osteoblast mineralization activity in vitro (*p < 0.05). Elevated PA intake significantly increased C16 ceramide accumulation. This accumulation was preventable through inhibition of SPT2 (serine palmitoyl transferase 2) using myriocin. Elevated levels of PA reduce osteoblast function in vitro and bone formation markers in vivo. Our findings suggest that saturated PA can compromise bone health by affecting osteoblasts, and identify a potential mechanism through which obesity promotes bone loss.

BACKGROUND

Hormonal and enzymatic factors may render certain individuals more susceptible to orthodontically induced inflammatory root resorption (OIIRR). The objectives of this study are (1) to identify biochemical key markers in blood and saliva that may be correlated to the trend of extensive OIIRR and (2) to utilise these markers to predict a susceptible patient-receiving orthodontic treatment.

METHODS

Nine patients (mean age 23 + 2.9 years) who had moderate to severe OIIRR that assessed via orthopantomograms and met the inclusion criteria were classified as the root resorption group (RRG). Blood chemistry was evaluated using the collection of fasting blood and unstimulated saliva samples. Multiplex enzyme-linked immunosorbent assay (ELISA) arrays were used to screen blood and saliva samples for human cytokines, chemokines and several key enzymes that may play a role in root resorption following orthodontic force application. Biochemical findings from 16 matching subjects were used as the control (CG) for comparative measurements.

RESULTS

Patients with moderate to severe OIIRR showed a significant increase in salivary cytokines including interleukin (IL) 7, IL-10, IL-12p70 and interferon-gamma (IFN-γ) level as well as a significant decrease in IL-4 level. Osteocalcin and procollagen type I N-terminal peptide (P1NP) appeared to be the only blood factors that showed a significant difference, more in the CG than the RRG.

CONCLUSIONS

Saliva might be a more valuable way of measuring changes in cytokine expression than blood secondary to orthodontic treatment. Although the increased expression of pro-inflammatory and anti-inflammatory cytokines may be determinants in the development of moderate to severe OIIRR, cytokine expression may be affected by several potential inflammations in another part of the body. Future research could investigate the cause/effect relationship of different cytokines, in a larger group of patients and at different time intervals, using digital subtraction radiography techniques and microfluidic biosensors.

This post hoc analysis of a randomized, double-blind study of postmenopausal women with osteoporosis found that there were early increases in bone turnover markers and decreases in bone mineral density after discontinuation of long-term alendronate. These findings might help guide treatment decisions, including monitoring after alendronate withdrawal.

Introduction: The short-term effects of discontinuing long-term bisphosphonates are poorly characterized. This post hoc analysis investigated 1-12-month changes in bone mineral density (BMD) and bone turnover markers (BTM) after alendronate (ALN) discontinuation.

Methods: Data were from a randomized, double-blind trial of MK-5442 (calcium-sensing receptor antagonist) following oral bisphosphonates, with placebo and continued ALN controls ( ClinicalTrials.gov NCT00996801). Postmenopausal women with osteoporosis had received oral bisphosphonate (≥ 3-4 preceding years; ALN for the 12 months pre-screening), continuing on ALN 70 mg/week (n = 87) or placebo (n = 88).

Results: At 12 months, least-squares mean percent changes from baseline BMD (placebo vs. ALN) were lumbar spine (LS): - 0.36 vs. 1.29, total hip: - 1.44 vs. 0.46, and femoral neck (FN): - 1.26 vs. - 0.08 (all P < 0.05). BTM levels increased by 1-3 months, to 12 months, with placebo vs. ALN (P < 0.001). FN BMD decline was greater in the placebo subgroup with higher urinary N-terminal cross-linked telopeptides of type I collagen/creatinine [uNTx/Cr] (P < 0.01), and higher serum N-terminal pro-peptide of type 1 collagen [P1NP] levels (P < 0.05), at baseline. There was a trend toward greater FN BMD loss with higher BTM levels at 3 and/or 6 months. Younger age and higher LS BMD at baseline were associated with greater LS BMD loss at 12 months (P = 0.04 and < 0.01, respectively); higher baseline FN BMD predicted greater FN BMD loss (P = 0.04).

Conclusion: Early changes in BTM levels and BMD were observed after discontinuation of long-term ALN. Further characterization of factors associated with patients' risk of bone loss upon bisphosphonate discontinuation is warranted.

Keywords: Alendronate; Bone mineral density; Discontinuation; Long-term; Oral bisphosphonates; Post hoc.