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.     

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     

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     

Biochemical Markers of Bone Turnover Reflect Femoral Bone Loss in Elderly Women

Although over 90% of hip fractures occur in patients over age 70, few data are available on femoral bone loss in this age group. To examine the relationship between biochemical markers of bone turnover and femoral bone loss in the elderly, 36 female and 17 male, healthy, community-dwelling elderly over age 65 (mean ± SD age: women 71 ± 4 years, men 75 ± 5 years) were followed for 3 years. Annual bone mineral density measurements of the hip and lumbar spine by dual-energy x-ray absorptiometry (DXA) were obtained and biochemical markers of bone resorption (urinary N-telopeptide crosslinks, free pyridinoline, total pyridinoline, total deoxypyridinoline, and hydroxyproline) and bone formation (serum osteocalcin, bone-specific alkaline phosphatase) were obtained at the end of year 3. In elderly women, longitudinal bone loss at the total hip was negatively correlated with markers of bone resorption (r =−0.39 to −0.52, P < 0.05), bone formation (r =−0.38, P < 0.05), and age (r =−0.39, P < 0.05). Markers of bone resorption were correlated with markers of bone formation (r = 0.63 to 0.74, P < 0.01). In multiple regression analysis, urinary N-telopeptide crosslinks (marker of resorption), serum osteocalcin (marker of formation), and serum parathyroid hormone explained 43% of the variability of bone loss at the total hip in women. These parameters were not related to bone loss in men. We conclude that femoral bone loss increases with age in women over 65. Measurements of specific biochemical markers of bone turnover are correlated with longitudinal bone loss in elderly women. These markers may help identify women at greatest risk for bone loss who would benefit most from therapeutic interventions. Received: 28 January 1996 / Accepted: 3 May 1996     

Evaluation of Ability of Biochemical Markers of Bone Turnover to Predict a Response to Increased Doses of HRT

Antiresorptive therapy is usually given in a fixed dose, and we hypothesized that some patients receiving standard doses of hormone replacement therapy (HRT) might benefit from a higher dose, particularly if their bone turnover decreases after increasing the dose of HRT. Eighty-eight women who had been receiving standard-dose (0.625 mg/day) conjugated equine estrogens (CEE) for at least one year were randomized to take either standard-dose (0.625 mg/day, n = 36) or high-dose (1.25 mg/day, n = 52) therapy. Subjects with a uterus were allowed to take either 10 mg of medroxyprogesterone cyclically or 5 mg daily, according to personal preference. Bone Mineral Density (BMD) and biochemical markers of bone turnover were followed for 2 years. Mean bone turnover decreased significantly (–4.1% to –19.1%) after 6 months of high-dose CEE. Decreases in serum BSAP (bone-specific alkaline phosphatase) and serum or urine NTX (N-terminal telopeptide crosslink of type I collagen) on high-dose therapy were not predictive of an improvement in BMD, but a decrease in serum CrossLaps did predict an improvement in BMD. Mean change in BMD in subjects with a significant decrease in serum CrossLaps at the anteroposterior spine was 3.1% ± 3.9% versus 1.2% ± 2.9% for subjects with no significant change in CrossLaps, P < 0.02. There was, however, a wide range of changes in BMD in patients with or without a significant change in CTX on high-dose HRT, making it impossible to predict an improvement in BMD based on an individuals changes in turnover. Measuring of bone density and bone turnover with better precision might be more successful in guiding individual dosing of antiresorptive therapy.This work is supported by a grant from the National Institutes of Health, grant #5 K08 AG000680-04; and from the William H. Milton Fund, Harvard Medical School, Boston, MA; and from Eli Lilly and Company, Indianapolis, IN; and from Mission Pharmacal, San Antonio, TX; and from the Upjohn Company, Kalamazoo, MI; and by NCRR grant RR 01032 supporting the General Clinical Research Center of Beth Israel Deaconess Medical Center.     

前列腺癌骨转移患者血清骨转换标志物的意义

目的:评价骨转换标志物在检测前列腺癌患者骨转移中的诊断准确性,并评价这些标志物作为预测前列腺癌患者死亡率指标的价值.