Bone Turnover Markers Do Not Predict Fracture Risk in Type 2 Diabetes

Type 2 diabetes (T2D) is characterized by increased fracture risk despite higher BMD and reduced bone turnover. BMD underestimates fracture risk in T2D, but the predictive role of bone turnover markers (BTMs) on fracture risk in T2D has not been explored. Thus, we sought to determine whether BTMs predict incident fractures in subjects with T2D. For this case-cohort study, we used data from the Health, Aging, and Body Composition (Health ABC) Study of well-functioning older adults, aged 70 to 79 years at baseline (April 1997–June 1998). The case-cohort sample consisted of (i) the cases, composed of all 223 participants who experienced incident fractures of the hip, clinical spine, or distal forearm within the first 9 years of study follow-up; and (ii) the subcohort of 508 randomly sampled participants from three strata at baseline (T2D, prediabetes, and normoglycemia) from the entire Health ABC cohort. A total of 690 subjects (223 cases, of whom 41 were in the subcohort) were included in analyses. BTMs (C-terminal telopeptide of type I collagen [CTX], osteocalcin [OC], and procollagen type 1 N-terminal propeptide [P1NP]) were measured in archived baseline serum. Cox regression with robust variance estimation was used to estimate the adjusted hazard ratio (HR) for fracture per 20% increase in BTMs. In nondiabetes (prediabetes plus normoglycemia), fracture risk was increased with higher CTX (HR 1.10; 95% confidence interval [CI], 1.01 to 1.20 for each 20% increase in CTX). Risk was not increased in T2D (HR 0.92; 95% CI, 0.81 to 1.04; p for interaction .045). Similarly, both OC and P1NP were associated with higher risk of fracture in nondiabetes, but not in T2D, with p for interaction of .078 and .109, respectively. In conclusion, BTMs did not predict incident fracture risk in T2D but were modestly associated with fracture risk in nondiabetes. © 2020 American Society for Bone and Mineral Research.     

Bone Turnover Markers in Primary Hyperparathyroidism

Primary hyperparathyroidism is an endocrine disorder characterized by elevated or inappropriate normal levels of parathyroid hormone in a setting of hypercalcemia. The inclusion of calcium on the basic metabolic bone panel has allowed this disorder to be diagnosed even in the absence of symptoms. Nevertheless, the skeleton can be a target of excess parathyroid hormone activity even during its asymptomatic presentation. Bone turnover markers a surrogate index of the process of the remodeling process at the level of bone, and thus can be useful to monitor skeleton involvement in primary hyperparathyroidism.     

Clinical Use of Bone Turnover Markers to Monitor Pharmacologic Fracture Prevention Therapy

Monitoring of drug therapies to prevent fractures is controversial. Measurement of bone turnover markers has the potential to identify those with a suboptimal response to fracture prevention medication within a few months of its commencement. However, given the imprecision of currently commercially available assays of bone turnover markers, many individual persons who are “suboptimal medication responders” are likely to be misclassified as “adequate responders” or vice versa, depending on the cut point chosen to define suboptimal and adequate response. Before bone turnover markers can be recommended for routine use in clinical practice to monitor fracture prevention therapies, three advances are needed: 1) bone marker assays with better precision; 2) research establishing optimal cut points of bone marker levels to distinguish “suboptimal responders” from “adequate responders”; and 3) research establishing the incremental fracture reduction benefit from clinical interventions for “suboptimal responders” identified from bone marker measurements.     

A Meta-Analysis of Reference Markers of Bone Turnover for Prediction of Fracture

The aim of this report was to summarize the clinical performance of two reference bone turnover markers (BTMs) in the prediction of fracture risk. We used an updated systematic review to examine the performance characteristics of serum procollagen type I N propeptide (s-PINP) and serum C-terminal cross-linking telopeptide of type I collagen (s-CTX) in fracture risk prediction in untreated individuals in prospective cohort studies. We excluded cross-sectional studies. Ten potentially eligible publications were identified and six included in the meta-analysis. There was a significant association between s-PINP and the risk of fracture. The hazard ratio per SD increase in s-PINP (gradient of risk [GR]) was 1.23 (95 % CI 1.09–1.39) for men and women combined unadjusted for bone mineral density. There was also a significant association between s-CTX and risk of fracture, GR = 1.18 (95 % CI 1.05–1.34) unadjusted for bone mineral density. For the outcome of hip fracture, the association between s-CTX and risk of fracture was slightly higher, 1.23 (95 % CI 1.04–1.47). Thus, there is a modest but significant association between BTMs and risk of future fractures.     

Nitrates Do Not Affect Bone Density or Bone Turnover in Postmenopausal Women: A Randomized Controlled Trial

Organic nitrates have been reported to have significant effects on bone mineral density (BMD) and bone turnover in previous clinical trials. However, results are inconsistent and some trials with strikingly positive results have been retracted because of scientific misconduct. As preparation for a potential fracture prevention study, we set out to determine the lowest effective dose and the most effective and acceptable nitrate preparation. We undertook a 1-year, double-blind, randomized, placebo-controlled trial of three different nitrate preparations and two different doses in osteopenic postmenopausal women, with a planned 1-year observational extension. The primary endpoint was change in BMD at the lumbar spine, and secondary endpoints included BMD changes at other sites, changes in bone turnover markers, and adverse events. A total of 240 eligible women who tolerated low-dose oral nitrate treatment in a 2-week run-in period were randomized to five different treatment groups or placebo. Over 12 months, there were no statistically significant between-group differences in changes in BMD at any site and no consistent differences in bone turnover markers. When the active treatment groups were pooled, there were also no differences in changes in BMD or bone turnover markers between nitrate treatment and placebo. Eighty-eight (27%) women withdrew during the run-in phase, with the majority because of nitrate-induced headache, and 41 of 200 (21%) women randomized to nitrate treatment withdrew or stopped study medication during the 1-year study compared with 1 of 40 (2.5%) in the placebo group. In summary, organic nitrates do not have clinically relevant effects on BMD or bone turnover in postmenopausal women and were poorly tolerated. These results call into question the validity of previous clinical research reporting large positive effects of nitrates on BMD and bone turnover. © 2020 American Society for Bone and Mineral Research.     

Biochemical Markers of Bone Turnover in Men

Although osteoporosis in men has been recently recognized as a public health problem, the mechanisms leading to bone loss are still poorly understood. Longitudinal studies of bone mineral density suggest an acceleration of bone loss after 70 years of age. Histomorphometric data concerning age-related changes of bone turnover in men are limited, including few men over 70 years and have been restricted to the trabecular envelope of bone biopsies. Most measurements of biochemical markers of bone turnover have been performed in small cohorts of limited age range, and results obtained in large cohorts are scanty. Levels of markers of bone formation and of bone resorption are very high in men aged 20-30 years which corresponds to the late phase of formation of peak bone mass, and then declines, reaching their lowest levels between 50 and 60 years. Data on bone turnover markers in elderly men are discordant. Concentrations of bone formation markers remain stable, decrease slightly, or even increase marginally. Markers of bone resorption increase in some studies, mainly after 70 years of age, in line with acceleration of bone loss in this age range. This discordance between studies can result from different reasons. The increase of bone turnover may be limited to a subgroup of elderly men. In addition, urinary levels of bone resorption markers depend on the rate of bone turnover, on pre-renal and renal catabolism of peptides released from bone matrix, on glomerular filtration rate, as well as unit of expression of their results (per 24 hours per urinary creatinine mass, per glomerular filtrate volume). In elderly men, biochemical bone markers are negatively correlated with bone mineral density. Longitudinal studies are not yet available on the relationship among bone turnover markers, rate of bone loss, and fracture. In conclusion, in elderly men, age-related bone loss seems to result from increased bone resorption which is not matched by increased bone formation. Thus, antiresorptive therapy may be of interest in the prevention and treatment of osteoporosis in men. Further studies are necessary to determine if bone resorption markers predict the risk of fragility fractures in elderly men.     

Short-Term Increases in Bone Turnover Markers Predict Parathyroid Hormone-Induced Spinal Bone Mineral Density Gains in Postmenopausal Women with Glucocorticoid-Induced Osteoporosis

The purpose of this study was to test the ability of early changes in markers of bone turnover to predict subsequent changes in bone mineral density (BMD) induced by parathyroid hormone fragment, PTH (1–34), in postmenopausal osteoporotic women treated with estrogen and glucocorticoids. Forty-nine postmenopausal women with chronic, inflammatory diseases and BMD T-scores ≤–2.5 at the lumbar spine or femoral neck who were concurrently treated with estrogen ≥ 1 year and prednisone 5–20 mg/day for ≥ 1 year participated. Subjects were randomized to treatment with human PTH (1–34) 400 IU/day or to a control group for 1 year and followed for an additional year. Serum and urine were collected at baseline and 1, 3, 6, 9, 12, 18 and 24 months for measurement of bone alkaline phosphatase (BAP), osteocalcin (OC) and deoxypyridinoline (DPD). We constructed an Uncoupling Index (UI) from all three markers (UI = [Z _BAP+Z _OC]/2 –Z _DPD, where the Z-score for each marker in each subject was calculated from the mean and standard deviation of the study population at baseline). BMD of the lumbar spine and hip was measured at baseline and every 6 months thereafter by dual-energy X-ray absorptiometry (DXA) and annually by quantitative computed tomography (QCT; spine only). BMD of the spine, but not hip (total, femoral neck or trochanter), and levels of all three markers increased significantly as a result of PTH treatment (p<0.01 compared with controls). The resorption response lagged behind that of formation as evidenced by a significant increase (p<0.05) in the UI for the first 9 months of treatment. The UI values and changes from baseline to 1, 3 and 6 months in BAP, OC and DPD were correlated with the 12- and 24-month changes in spine BMD measured both with QCT and with DXA (Spearman’s rank coefficients ≤0.76; p<0.05). Most PTH-treated subjects could be identified as biochemical responders by least significant change analysis. Following 1 month of therapy, BAP and OC identified 65% and 81% as responders, respectively. The responder rates were 79%, 79% and 75% for BAP, OC and DPD, respectively by 6 months. Responders exhibited a high level of diagnostic accuracy for predicting a gain in BMD (areas under the receiver operating characteristic curves exceeding 0.79 for QCT and 0.70 for DXA), but not the magnitude of the gain. These data suggest that serial bone marker measurements may be useful in identifying skeletal responders to an anabolic therapy, such as PTH, in estrogen-replete postmenopausal women with glucocorticoid-induced osteoporosis. Received: 27 July 1999 / Accepted: 2 November 1999     

Race and Ethnicity Predict Bone Markers and Fracture in Pediatric Patients With Chronic Kidney Disease

Studies in healthy children have shown racial-ethnic differences in bone markers and bone outcomes including fractures. At present, limited studies have evaluated the impact of race and ethnicity on bone markers and fractures within the pediatric chronic kidney disease (CKD) population. In a cohort study of 762 children between the ages of 1.5 years and 18 years, with CKD stages 1 to 4 from the CKD in children (CKiD) cohort, the relationship between racial-ethnic group and bone markers (parathyroid hormone [PTH], 25-hydroxyvitamin D [25-OHD], 1,25-dihydroxyvitamin D [1,25(OH)₂D], and C-terminal fibroblast growth factor [FGF23]) was determined using linear mixed models. Additionally, logistic regression was used to evaluate racial-ethnic differences in prevalent fracture upon study entry. Black race was associated with 23% higher PTH levels (confidence interval [CI], 2.5% to 47.7%; p = .03), 33.1% lower 25-OHD levels (CI, −39.7% to −25.7%; p < .0001), and no difference in C-terminal FGF23 or 1,25(OH)₂D levels when compared to whites. Hispanic ethnicity was associated with 15.9% lower C-terminal FGF23 levels (CI, −28.3% to −1.5%; p = .03) and 13.8% lower 25-OHD levels (CI, −22.2% to −4.5%; p = .005) when compared to whites. Black and Hispanic children had 74% (odds ratio [OR] 0.26; CI, 0.14 to 0.49; p = .001) and 66% (OR 0.34; CI, 0.17 to 0.65; p < .0001) lower odds of any fracture than white children at study entry, respectively. Race and ethnicity are associated with differences in bone markers and despite lower 25-OHD levels, both black and Hispanic children with CKD reported a lower prevalent fracture history than white children. The current findings in the CKD population are similar to racial-ethnic differences described in healthy children. Additional studies are needed to better understand how these differences might impact the management of pediatric CKD-MBD. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Inflammation and Bone Turnover Markers in Adult Obesity

Obesity is a condition of abnormally increased body fat resulting from increased energy intake relative to energy expenditure. Excess body weight is a risk factor for many somatic and psychological disorders, including cardiovascular disease, type 2 diabetes mellitus, osteoarthritis, and cancer types. Bone metabolism, bone turnover, and mineral content are altered in severe obesity. This review will focus on the relationship between inflammation and bone biomarkers in adult obesity.     

Biochemical Markers of Bone Turnover,Hip Bone Loss,and Fracture in Older Men: The MrOS Study

We used data from the Osteoporotic Fractures in Men (MrOS) study to test the hypothesis that men with higher levels of bone turnover would have accelerated bone loss and an elevated risk of fracture. MrOS enrolled 5995 subjects >65 yr; hip BMD was measured at baseline and after a mean follow‐up of 4.6 yr. Nonspine fractures were documented during a mean follow‐up of 5.0 yr. Using fasting serum collected at baseline and stored at ?190°C, bone turnover measurements (type I collagen N‐propeptide [PINP]; β C‐terminal cross‐linked telopeptide of type I collagen [βCTX]; and TRACP5b) were obtained on 384 men with nonspine fracture (including 72 hip fractures) and 947 men selected at random. Among randomly selected men, total hip bone loss was 0.5%/yr among those in the highest quartile of PINP (>44.3 ng/ml) and 0.3%/yr among those in the lower three quartiles (p = 0.01). Fracture risk was elevated among men in the highest quartile of PINP (hip fracture relative hazard = 2.13; 95% CI: 1.23, 3.68; nonspine relative hazard = 1.57, 95% CI: 1.21, 2.05) or βCTX (hip fracture relative hazard = 1.76, 95 CI: 1.04, 2.98; nonspine relative hazard = 1.29, 95% CI: 0.99, 1.69) but not TRACP5b. Further adjustment for baseline hip BMD eliminated all associations between bone turnover and fracture. We conclude that higher levels of bone turnover are associated with greater hip bone loss in older men, but increased turnover is not independently associated with the risk of hip or nonspine fracture.     

Changes in Bone Mass and Bone Turnover Following Ankle Fracture

Bone loss and increased bone turnover are recognized local changes after a fracture, but the exact patterns of these changes after different fractures are unclear. We aimed to investigate the changes in bone density and biochemical markers following ankle fracture. Fourteen subjects (7 postmenopausal women and 7 men, mean age 63 years) were recruited following fracture of the distal tibia and fibula. Bone mineral density (BMD) of the ankle and proximal femur were measured by dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) of the calcaneus at 0, 6, 12, 26 and 52 weeks after fracture. Serum and urine samples were collected at 0, 3 and 7 days and at 2, 4, 6, 12, 26 and 52 weeks after fracture to measure markers of bone turnover. For bone formation we measured: bone alkaline phosphatase (iBAP), osteocalcin (Oc), procollagen type I N-terminal propeptide (PINP); and for bone resorption: tartrate-resistant acid phosphatase (TRAcP), deoxypyridinoline (iFDpd), N-telopeptides of type I collagen (NTx). We used the nonfractured limb to calculate values for baseline BMD and QUS. There was a significant decrease in BMD at the ultradistal ankle (p<0.001), the trochanteric region of the hip (p<0.01) and QUS of the heel after ankle fracture. This bone loss was maximal for ultradistal ankle BMD by 6 weeks at 13% (p<0.001) and for the trochanter by 26 weeks at 3% (p<0.01). The ankle BMD returned to baseline at 52 weeks but the trochanter BMD did not. Velocity of sound (VOS) decreased at 6 weeks by 2% (p<0.01) and broadband ultrasound attenuation (BUA) by 15% (p<0.01). VOS recovered completely by 52 weeks, but BUA did not return to baseline. Bone formation markers increased significantly between 1 and 4 weeks by 11–78% (p<0.01), and iBAP returned to baseline at 52 weeks but PINP and Oc remained elevated. Bone resorption markers did not increase and NTx was decreased at 52 weeks. We conclude that BMD decreased distal and immediately proximal to the fracture line when measured with DXA and QUS. Ankle BMD and heel VOS recovered at 52 weeks (trochanteric BMD and heel BUA did not) and the bone turnover markers returned toward baseline. Received: 27 January 1999 / Accepted: 19 April 1999     

Stress Fracture of the Proximal Fibula in Military Recruits

Background

We wanted to report on stress fracture of the proximal fibula and to suggest the pathomechanism of this fracture.

Methods

Between April 2004 through April 2005, the military recruits who complained of leg pain during the 6 weeks basic training in the Republic of Korea Marine Corps education and training group were evaluated according to their clinical manifestations and plain radiographs.

Results

Twelve recruits of 635 recruits who complained leg pain were diagnosed as having fibular stress fracture. Eleven cases (10 recruits) appeared at the junction of the proximal and middle 1/3 of the fibula and 2 cases (2 recruits) were in the middle 1/3 of the fibula, as assessed radiologically. Tenderness was the most reliable clinical manifestation. All the fractures occurred after repetitive walking or jumping in a squatting position. Conservative treatments that included bed rest, immobilization and non-steroidal anti-inflammatory drugs administration according to the symptom severity were satisfactory.

Conclusions

Proximal fibular stress fracture is not rare in military recruits. The shearing force on the proximal fibula and the repetitive stress by walking or jumping in a squatting position contribute to the stress fracture of the proximal fibula.     

Relationships Between Changes in Bone Mineral Density or Bone Turnover Markers and Vertebral Fracture Incidence in Patients Treated with Bazedoxifene

We analyzed the relationships between bone mineral density (BMD) or bone turnover marker (BTM) changes and vertebral fracture incidence in women treated with bazedoxifene using a post hoc analysis from a 3-year randomized, placebo-controlled study evaluating the effect of bazedoxifene (20 or 40?mg) on fracture risk reduction. BMD was assessed at baseline and every 6?months for 3?years. Osteocalcin and C-telopeptide of type I collagen were assessed at baseline and at 3, 12, and 36?months. Vertebral fractures were assessed with a semiquantitative visual assessment. Data were available for 5,244 women, of whom 3,476 were treated with bazedoxifene. Using a logistic regression analysis and the classical Li approach, the proportion of fracture incidence explained by BMD change after 3?years of bazedoxifene treatment was 29?% for the total hip and 44?% for the femoral neck. The proportion of treatment explained by lumbar BMD change could not be quantified accurately because of the significant interaction between treatment and change in BMD. With the same model, the 12-month BTM changes explained up to 29?% of the fracture risk reduction observed with the two forms of bazedoxifene. In women treated with bazedoxifene, changes in femoral neck BMD, hip BMD, or BTMs explained a moderate proportion of the fracture risk reduction observed during the 3?years of follow-up. However, BMD or BTM changes cannot be recommended for individual monitoring of women treated with bazedoxifene.     

Determinants of Bone Turnover Markers in Healthy Premenopausal Women

Bone turnover markers (BTMs) are widely used for the management of osteoporosis, and the premenopausal reference range is the target value for the treatment of postmenopausal osteoporosis with antiresorbing agents. Three serum BTMs (serum C-telopeptide of type I collagen [CTX], osteocalcin [OC], and N-terminal propeptide of type I procollagen [P1NP]), serum calcium, creatinine, phosphate, magnesium, and follicle-stimulating hormone (FSH) were measured in 638 healthy premenopausal women aged 20-50 years. In 83 women on the contraceptive pill (CP), the levels of the three BTMs adjusted for all confounding factors were 14-26% lower (P < 0.005) than in non-CP users. In 18 women considered perimenopausal for serum FSH levels >30 IU/mL despite having regular menses, BTM levels were significantly higher than in age-matched women. This group of subjects and the women on the CP were excluded from further analysis. The three BTMs significantly decreased with advancing age and were negatively and independently correlated with body mass index (P < 0.001) and serum phosphate. In conclusion, we confirm that CP use is associated with significantly lower BTM values. An increase in BTM concentrations can be observed in perimenopausal women, i.e., women with normal menses but FSH levels >30 IU/mL. BTMs decrease substantially with advancing age, and this appears to be associated with changes in body weight and serum phosphate. New normative ranges for serum OC, CTX, and P1NP were identified; and our findings in general impose a redefinition of the criteria for establishing the normal ranges for BTMs.     

Changes in Bone Mass and Bone Turnover Following Distal Forearm Fracture

Bone loss occurs close to a fracture and is associated with increased bone turnover. Fracture healing itself results in increased markers of bone turnover. But the exact patterns of these changes after different fractures are unclear. We aimed to investigate the changes in bone density and biochemical markers following distal forearm fracture. Twenty women (mean age 63 years) were recruited following fracture of the distal radius and ulna. Bone mineral density (BMD) of the hand and forearm were measured by dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) of the fingers was measured at 0, 6, 12, 26 and 52 weeks after fracture. Serum and urine samples were collected at 0, 3 and 7 days and at 2, 4, 6, 12, 26 and 52 weeks after fracture to measure markers of bone turnover. For bone formation we measured: bone alkaline phosphatase (iBAP), osteocalcin (Oc), procollagen type I N-terminal propeptide (PINP); and for bone resorption: tartrate-resistant acid phosphatase (TRAcP), free deoxypyridinoline (iFDpd), N-telopeptides of type I collagen (NTx). We used the nonfractured limb to calculate values for baseline BMD and amplitude-dependent speed of sound (AD-SoS). There was a decrease in BMD at the hand and in AD-SoS of the fingers after forearm fracture (p<0.001). This bone loss was maximal for BMD by 6 weeks at 9% (p<0.001) and remained decreased at 52 weeks. AD-SoS decreased at 12 weeks by 3% (p<0.01) and recovered completely by 52 weeks. Bone formation markers increased between 2 and 4 weeks by 13–52% (p<0.001), and were still elevated at 52 weeks. Bone resorption markers increased between 2 and 6 weeks by 18–35% and returned to baseline at 52 weeks (TRAcP remained elevated). We conclude that BMD decreased distal and immediately proximal to the fracture line when measured with DXA and QUS. Bone loss after distal forearm fracture did not recover by 52 weeks and most bone turnover markers did not return to baseline. Received: 27 January 1999 / Accepted: 19 April 1999