Clinical application of bone metabolism markers to disuse bone atrophy

Mechanical stress on bone is one of the determinants of bone morphology, bone mineral density and bone strength. Therefore, disuse accelerates bone resorption, especially of cancellous bone, and consequently bone becomes atrophic and fragile. Osteocytes embedded in the bone matrix respond to mechanical load and changes of bone metabolism. The gapjunction of the long processes of osteocytes plays an important role in transmitting mechanical load through intracellular signal transmitters (cAMP, cGMP) and extracellular signal transmitters (PGE(2), IGF- I , IGF- II , TGF-beta) , to induce bone formation by osteoblasts and bone resorption by osteoclasts, or a combination of the two. Bone metabolism markers reflect activities of osteoblasts and osteoclasts, so they provide information on bone turnover and bone metabolism. Bone resorption markers characteristically increase and remain high during bed rest and disuse, whereas ambulation and exercise, as in kinesiotherapy, decrease bone resorption markers. As for treatments of disuse bone atrophy, from the bone metabolic and pharmacological viewpoint, anti-resorption agents are recommended to inhibit bone loss. Bisphosphonates which are strong anti-resorption agents, are expected to inhibit bone resorption. Calcitonin and vitamin K(2) which are also anti-resorption agents effectively, reduce bone loss due to disuse and bed rest.     

Menopause and bone metabolism

Hypoestrogenemia in climacterium causes high turnover bone metabolism, relative dominance of bone resorption, and osteopenia. Women have severe bone loss in climacterium. The objective for the prevention of osteoporosis in this period is to detect the high risk women of osteoporosis with bone mineral densitometry or bone metabolic markers and to start the preventive therapy, i. e. food, exercise and drug, as soon as possible. Therefore, menopause is very important period to prevent osteoporosis in future.     

Results of bone scintigraphy,densitometry and radiography in secondary hyperparathyroidism in patients with chronic renal failure

Secondary hyperparathyroidism occurs frequently in patients with chronic renal failure (CRF). Cardinal manifestations in patients with secondary hyperparathyroidism involve also skeletal changes. Hence the aims of our studies were detailed investigations of bones using isotope scintigraphy (99mTc-MDP), densitometry (DEXA-Lunar) and radiography, in a group of 34 patients with advanced secondary hyperparathyroidism with very high PTH serum concentrations. Bone mineral density of radius amounted to 74.14 +/- 14%, and 29 cases had osteoporosis, and 5 cases osteopenia. Bone mineral density of vertebral bodies was 85.6 +/- 10.5% was within osteopenia range in 16 cases, osteoporosis in 11 cases and was normal in 6 cases. Bone scintigraphy revealed: excessive tracer uptake in cranial vault, mandible, spine and lateral parts of the sacral bone. Tracer accumulation was decreased in soft tissues and absent in kidneys. Roentgen studies revealed changes typical to secondary hyperparathyroidism: acroosteolysis in 60% of cases, subperiosteal resorption in 43% of cases, calcifications in 20% of cases, cortical fibrosis in 35% of cases and osteoporosis in 85% of cases. CONCLUSIONS: 1. Bone mineral density is markly decreased in the radius and to a lower extent in the vertebral bodies, hence DEXA studies of radius are most appropriate for evaluation of mineral bone density. The differences in BMD are characteristic of hyperparathyroidism, both primary and secondary. 2. In most patients bone scintigraphy shows characteristic abnormalities, thus scintigraphy is helpful in the diagnosis of advanced secondary hyperparathyroidism. 3. In x-ray studies osteoporosis is frequently observed, other signs of secondary hyperparathyroidism are not so common and appear in later stage of disease than decreased bone mineral density in densitometry.     

Bone mineral density in primary hyperparathyroidism

Skeletal complications of advanced hyperparathyroidism include clinically bone pains, muscle weakness, bone deformities and fractures. X-ray studies reveal subperiosteal bone resorption, atrophy of the cortex of long bones, cysts, brown tumours and calcifications of soft tissues; these changes appear in the late period of the disease. In recent onset of hyperparathyroidism bone changes may be detected by X-ray absorptiometry. Thus the aim of our study was to evaluate bone mineral density with the use of dual energy X-ray absorptiometry (DEXA) at two sites: in lumbar vertebral bodies consisting mainly of the trabecular bone and in 1/3 distal part of the radius composed predominantly of the cortical bone. Twenty-three patients with primary hyperparathyroidism were included in our study. Hypercalcemia (ionized calcium above 5.4 mg/100 ml, total calcium above 10.6 mg/100 ml) and increased serum PTH, above 100 pg/ml, were detected in all patients. Isotope scintigraphy using 99mTc-MIBI revealed the presence of a parathyroid adenoma; this was confirmed at surgery and histopathologically. In bone densitometry we found greatly reduced bone mineral density (BMD) in 1/3 distal part of the radius amounting to 66.8 +/- 12.0% of the age-matched range and markedly smaller bone loss in lumbar spine, BMD was 91.7 +/- 14.6%. In 10 patients control densitometry, performed 6-24 months after parathyroid adenomectomy, revealed a marked 10 to 22% increase in bone density of lumbar vertebral bodies in the first year. BMD of the 1/3 distal part of the radius increased to a smaller degree 6.3% per year. CONCLUSIONS: 1. Bone densitometry in primary hyperparathyroidism reveals pronounced decrease in bone mineral density in the 1/3 distal part of the radius and much smaller decrease of the lumbar spine density. 2. Parathyroid adenomectomy leads to a rapid increase in density of the trabecular bone L1-L4 vertebral bodies and much smaller increase in the cortical bone of the radius. 3. Pronounced differences in bone mineral density of cortical bone and trabecular bone surpassing 20% are characteristic of hyperparathyroidism as they do not occur in other types of osteoporosis.     

Biochemical markers and bone densitometry in inflammatory bowel disease.

AIMS: Bone mineral density is reduced in patients with inflammatory bowel disease. The possible causes of this situation are delayed puberty, malabsorption, and corticosteroid use, among others. No published data exist regarding the use of biochemical markers and bone densitometry to assess osteopenia in these patients in Spain. METHODS: We studied 54 patients (24 men and 30 women), 22 with Crohn's disease and 32 with ulcerative colitis. Age, type of disease and average daily dose of prednisone-equivalent corticosteroids were evaluated. Lumbar bone mineral density was assessed quantitative digital radiography densitometry. The bone resorption marker urine D-pyridinoline and the bone formation marker serum osteocalcin were also assessed. RESULTS: Mean age was 36.61 +/- 13.37 years. Daily corticosteroid dose was correlated with D-pyridinoline (r = 0.413; p < 0.01), and D-pyridinoline was inversely correlated with osteocalcin (r = -0.304; p < 0.01). There was a negative correlation between bone mineral density and corticosteroid dose. There was no relationship between biochemical markers and bone densitometry findings in these patients. There were no differences in terms of bone densitometry findings or biochemical markers between the two types of inflammatory bowel disease. CONCLUSIONS: D-pyridinoline correlated inversely with osteocalcin. Daily corticosteroid dose correlated directly with D-pyridinoline, and inversely with bone mineral density.     

Low estrogen and high parathyroid hormone-related peptide levels contribute to accelerated bone resorption and bone loss in lactating mice

Providing enough calcium for milk production stresses calcium homeostasis in lactating mammals. A universal response to these demands for calcium appears to be the mobilization of maternal skeletal reserves, and bone loss during lactation has been well documented. However, the regulation of calcium and skeletal metabolism during lactation remains enigmatic. Our study was designed to examine mineral and bone metabolism in lactating mice. We found that mice lose bone rapidly at all sites during lactation. Bone mineral density as determined by dual-energy x-ray absorptiometry was 20 to 30% lower at the spine, femur, and total body in lactating compared with either age-matched virgin or pregnant mice. The decrease in bone mineral density was accompanied by dramatic reductions in bone volume and changes in trabecular architecture. Bone loss was also accompanied by increases in bone turnover as determined by biochemical markers and histomorphometry. PTHrP levels were elevated during lactation and correlated positively with markers of bone resorption and negatively with bone mass at all sites. Estrogen levels were low during lactation and correlated negatively with bone resorption markers. Finally, estrogen and pamidronate treatment lowered rates of bone resorption to baseline virgin levels and mitigated, but did not prevent, bone loss. These data suggest that the combination of estrogen deficiency and elevations in circulating PTHrP during lactation act to stimulate bone resorption and promote bone loss.     

Predictive factors for bone loss

A clear understanding of the pattern and determinants of bone loss in later life is required to the design of preventive strategies against osteoporosis. However, there have been few longitudinal studies of changes in bone mineral density (BMD) in the general population. The objective of this review was to characterise the determinants of bone loss and assess whether they could predict the bone loss in the future. Aging, female sex, perimenopausal period were significantly associated with the rate of bone loss. Anthropometric measurements at baseline were also related significantly to change in bone density. Baseline values and the change of weight, height and BMI were statistically significant predictors for bone loss. By contrast, longitudinal cohort study showed the difference of residence was no longer associated with the bone loss. Furthermore, what the rate of bone change was different from birth cohort was introduced. Thus, the comparison of the data obtained in same strata at the present and 10 years ago, there were significant generation gaps in men in their 60s and in women in their 50s. Concerning bone metabolic markers, some markers were significantly related to the change of lumbar BMD, however, the coefficient for determination for these markers in the prediction of bone loss was only less than 10%. It therefore was concluded that bone metabolic markers might not be sufficiently helpful to predict the change of BMD in individuals. Other factors including new biochemical markers and lifestyle factors should be considered in a clinical diagnosis.     

Serum Sclerostin Increases in Healthy Adult Men during Bed Rest

Context: Animal models and human studies suggest that osteocytes regulate the skeleton's response to mechanical unloading in part by an increase in sclerostin. However, few studies have reported changes in serum sclerostin in humans exposed to reduced mechanical loading. Objective: We determined changes in serum sclerostin and bone turnover markers in healthy adult men undergoing controlled bed rest. Design, Setting, and Participants: Seven healthy adult men (31 ± 3 yr old) underwent 90 d of 6° head down tilt bed rest at the University of Texas Medical Branch Institute for Translational Sciences-Clinical Research Center. Outcomes: Serum sclerostin, PTH, vitamin D, bone resorption and formation markers, urinary calcium and phosphorus excretion, and 24-h pooled urinary markers of bone resorption were evaluated before bed rest [baseline (BL)] and at bed rest d 28 (BR-28), d 60 (BR-60), and d 90 (BR-90). Bone mineral density was measured at BL, BR-60, and 5 d after the end of the study (BR+5). Data are reported as mean ± sd. Results: Consistent with prior reports, bone mineral density declined significantly (1-2% per month) at weight-bearing skeletal sites. Serum sclerostin was elevated above BL at BR-28 (+29 ± 20%; P = 0.003) and BR-60 (+42 ± 31%; P < 0.001), with a lesser increase at BR-90 (+22 ± 21%; P = 0.07). Serum PTH levels were reduced at BR-28 (-17 ± 16%; P = 0.02) and BR-60 (-24 ± 14%; P = 0.03) and remained lower than BL at BR-90 (-21 ± 21%; P = 0.14), but did not reach statistical significance. Serum bone turnover markers were unchanged; however, urinary bone resorption markers and calcium were significantly elevated at all time points after bed rest (P < 0.01). Conclusions: In healthy men subjected to controlled bed rest for 90 d, serum sclerostin increased, with a peak at 60, whereas serum PTH declined, and urinary calcium and bone resorption markers increased.     

Assessment of the risk of post-menopausal osteoporosis using clinical factors

OBJECTIVE: We wished to assess the predictive value of the main clinical risk factors for osteoporosis over a low vertebral bone mineral density. DESIGN: A cross-sectional study was made of a cohort of peri and post-menopausal women (mean age, 54 years). PATIENTS: One thousand, five hundred and sixty-five normal white women were selected from among the women referred to our menopause clinic for screening and prevention of osteoporosis. MEASUREMENTS: Each woman had replied to a detailed standardized questionnaire including the main clinical risk factors and had her bone density measured using dual photon absorptiometry. RESULTS: The predictive value for a low vertebral bone mineral density (2 SD below the normal young adult value) was assessed for 15 historical and anthropometric variables. Among these, age, age at menarche, weight, height, menopause and its duration, were independent predictors of a low bone mineral density, in a multiple logistic regression analysis. Odds ratios were calculated for each of these variables, weight, menopause and its duration being the three most influential variables. At best this model makes it possible to correctly classify 73% of women with a low bone mineral density and 66% of those with a normal bone mineral density. If this model is used for screening, it could possibly save 25% of bone densitometry examinations. CONCLUSIONS: Direct bone densitometry remains indispensable to assess osteoporosis risk, since risk factors alone are not sufficient for accurate delineation of either low or normal bone mineral density.     

Effect of the diphosphonate EHDP on bone mineral metabolism during prolonged bed rest.

The effect of disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDPTM) on bone mineral metabolism was tested in 4 healthy young men during 20 weeks of continuous bed rest. Two subjects received an oral dose of 5 mg/kg/day and the other 2 20 mg/kg/day. The low dose had two minor effects: the increase in bone accretion rate which usually occurs during bed rest was prevented, and there was an accentuation of the bed rest induced increase in hydroxyproline excretion. Skeletal mineral loss, assessed by calcium balance measurements and gamma ray absorptiometry of the calcaneus, occurred at the rate previously noted in untreated control subjects. Two types of drug effect were apparent at the higher dosage: one was immediate and sustained--a rise in serum phosphorus concentration and a fall in serum alkaline phosphatase activity. The other was delayed and progressive--a decline in urinary hydroxyproline excretion and in the rates of bone accretion and resorption. Skeletal mineral loss may have been affected; the usual negative mineral balance developed during the first half of the study, then disappeared during the last few weeks. However, gamma ray absorptiometry revealed no attenuation of the calcaneal mineral losses.     

Role of biochemical markers in the management of osteoporosis

Several serum and urine biochemical markers of bone resorption and formation have been developed. Biochemical bone markers have been used as intermediate end-points in all major studies of anti-osteoporotic therapies. Bone resorption markers, in particular, may add an independent, predictive value to the assessment of bone loss and fracture risk. There are also potential advantages in monitoring anti-osteoporotic treatment in the short-term in addition to bone densitometry, to rapidly identify non-responders to therapy, or non-compliance. Despite these recent advances, until now bone markers have simply been very useful research tools, with their clinical utility being limited by intra-individual and diurnal variability. However, the probability of the true bone mineral density response to hormone replacement therapy for the individual patient may be predicted using algorithms based on a spectrum of cut-off bone marker levels with varying false positive and negative rates. Thus, the transition of biochemical bone markers into everyday clinical practice may be rapidly approaching.     

Approach to the prostate cancer patient with bone disease

Prostate cancer is the most common visceral malignancy in men. Androgen deprivation therapy (ADT) is commonly used in patients with nonmetastatic prostate cancer and is associated with significant bone loss and fractures. The greatest bone loss occurs during initiation of ADT. Men should have assessment of skeletal integrity with bone mineral density examination by dual x-ray absorptiometry of the hip and spine. Men with fragility fractures or osteoporosis by bone density should be considered for bisphosphonate therapy. Men with low bone mass may need antiresorptive therapy, depending on other risk factors. Men with a normal bone mineral density should be followed up closely with bone densitometry while on ADT. All men should receive preventive measures with calcium (1200 mg daily in divided doses), vitamin D (800-1000 IU/d), and weight-bearing exercise. Men should be evaluated for additional secondary causes of bone loss including vitamin D insufficiency. Guidelines are needed for androgen-induced bone loss screening and treatment.     

Estrogen receptor genotypes and their association with the 10-year changes in bone mineral density and osteocalcin concentrations

We conducted a 10-yr prospective study of peak bone mass and its change in 604 women, aged 24-44 yr at study initiation, and related changes in bone mineral density (BMD) and osteocalcin (OCN) concentrations to estrogen receptor (ER) alpha gene polymorphisms in 442 of these women. We examined the association of ER alpha PvuII and XbaI polymorphisms with the 10-yr change in lumbar spine (LS) and femoral neck (FN) BMD, measured by densitometry, as well as serum OCN levels, after accounting for weight and menstrual status change. The women were members of the Michigan Bone Health Study, a population-based longitudinal study of BMD. There was a linear loss of LS BMD and curvilinear loss of FN BMD from peak bone mass over a 10-yr period. Women homozygous for the ER alpha gene variant without an XbaI restriction site (XbaI -/- genotype) had higher FN BMD and less change in LS over time. Women homozygous for the ER alpha gene variant without a PvuII restriction site (PvuII -/- genotype) had less LS BMD change over time as well as higher FN BMD. However, this higher FN BMD was dependent upon the rate of bone turnover as estimated from serum OCN change over time. The ER alpha genotype associations were statistically significant in explaining the rate of perimenopausal bone loss and its turnover; however, BMI or becoming postmenopausal contributed more to the magnitude of the difference in bone change.     

Diagnosis and Management of Mineral Metabolism in CKD

BACKGROUND  

Chronic kidney disease (CKD) affects over 26 million Americans and is frequently complicated early in its course by disordered mineral metabolism and metabolic bone disease. Since CKD-related bone loss is often indistinguishable from osteoporosis by standard bone densitometry, many CKD patients may be inappropriately treated with bisphosphonates rather than CKD-specific therapies.     

Measurements of bone mass and bone density

X-ray-based procedures are available to measure bone mineral density in vitro at almost any skeletal site. These bone density measurements are not useful in the diagnosis of the cause of bone loss but at present are the only tests available for assessing bone mass prior to the occurrence of irreversible changes such as fractures or vertebral compression, which are easily recognizable on x-rays. When fractures are present, the severity of the bone loss and the risk for future fractures can be assessed. Repeated measurements permit estimation of the rate of bone loss, which gives useful information for monitoring treatment effect or course of the disease. Measurement of total body calcium is of less clinical importance because of the predominantly trabecular bone loss that generally occurs in metabolic bone disease. Dual-energy x-ray absorptiometry (DEXA) and quantitative computed tomography (QCT) of the spine are of about equal clinical value in the first approach to the patient with metabolic bone disease, although DEXA allows greater variety in sampling sites. For repeated measurements, DEXA provides better precision at significantly lower radiation burden. For bone mineral measurements, the lumbar spine appears to be the most sensitive skeletal site.     

Primary hyperparathyroidism.

Many studies of asymptomatic primary hyperparathyroidism by noninvasive bone densitometry are beginning to show that demineralization is relatively common. This patient showed a pattern that is most typical of primary hyperparathyroidism, namely, normal bone mineral density of the vertebral spine and significant reduction of bone mineral density of the distal radius.     

Hyperparathyroidism: the limits of surgery in cases of bone or cardiovascular involvement

In primary hyperparathyroidism (PHPT), asymptomatic bone disease can be detected by bone densitometry. The bone mineral density is about 10% lower than normal control values, especially in the cortical radius. Without parathyroidectomy, bone mineral density is frequently stable, but a few patients, mostly postmenopausal women, have a significant decrease. Histology shows maintenance of trabecular connectivity but with an increase in cortical porosity. After parathyroidectomy, bone mineral density increases, particularly at the lumbar spine and femoral neck, and the benefit persists after 10 years. The fracture risk is controversial but risk of trabecular bone fracture may be higher than that for controls. The impact of PHPT on survival is also controversial, but highest quartile of serum calcium, osteoporosis, old age, and low lean mass are each associated with a death risk. There is also a debate about the criteria for distinguishing between asymptomatic and symptomatic PHPT and about the bone mineral density threshold that should be used as a basis to recommend surgery. The rate of progression of PHPT is slow but in some cases bone loss progresses, justifying bone mineral density follow-up. The frequency of inadequate follow-up and the cost of nonoperative follow-up are in favor of recommending surgery. With broader indications for surgery, it is mandatory to improve the biochemical diagnosis of PHPT.     

Influence of the vitamin D receptor gene polymorphism on bone loss in men after liver transplantation

BACKGROUND: Bone loss is a frequent complication after liver transplantation. OBJECTIVE: To investigate whether vitamin D receptor gene polymorphism influences bone loss in men after liver transplantation. DESIGN: Prospective cohort study. SETTING: University hospital. PATIENTS: 55 male candidates for liver transplantation. MEASUREMENTS: Lumbar spine bone mineral density was measured before and 3, 6, 12, and 24 months after liver transplantation. Vitamin D receptor genotype was determined by restriction endonuclease Bsml. RESULTS: Vitamin D receptor genotypes were significantly associated with post-transplantation changes in bone mineral density (P = 0.028). Within 3 months after transplantation, patients with the genotypes Bb or BB showed a vertebral bone loss substantially greater than that in patients with the bb genotype (between-group difference in the percentage change with respect to baseline bone mineral density, 3.7% [95% CI, 0.6% to 6.9%1). In 3 to 24 months after transplantation, bone mineral density increased steadily in the three allelic groups. CONCLUSIONS: Vitamin D receptor gene polymorphism influences bone loss after liver transplantation. Patients with the bb genotype are, to some extent, protected against post-transplantation bone loss.     

IGF-1对去卵巢大鼠骨密度及骨力学强度的影响

目的 研究外源性胰岛素样生长因子-1(IGF-1)对去卵巢(OVX)骨质疏松大鼠骨密度、骨转换率、骨力学强度等方面的影响.方法 对大鼠施行双侧卵巢摘除术,术后3个月以骨密度测定证实骨质疏松的存在后,随机分为5组,分别以生理盐水、甲状旁腺激素1-34及3种不同剂量IGF-1进行干预.同时设立生理盐水干预的假手术大鼠作为对照.8周后检测血清钙、磷、骨钙素水平及碱性磷酸酶活性;测定腰椎骨密度、股骨力学强度;组织学染色测定股骨远端骨皮质厚度.结果 IGF-1虽未提高OVX大鼠腰椎骨密度却可以显著提高其股骨力学强度.血清学检测结果表明,IGF-1可降低血清钙、磷、骨钙素水平及碱性磷酸酶活性;组织学染色显示IGF-1可显著提高OVX大鼠股骨骨皮质厚度.结论 IGF-1可增加OVX大鼠股骨的力学强度,此作用可能是通过改善骨结构而非提高骨密度所实现的.     

Recovery from osteopenia in adolescent girls with anorexia nervosa

Osteopenia is a frequent complication of anorexia nervosa (AN). To determine whether the deficit in bone mineral changes during the course of this illness, we studied 15 adolescent patients prospectively for 12-16 months using dual photon absorptiometry of the spine and whole body. At follow-up, mean weight, height, and body mass index (BMI) had increased significantly, although 6 girls had further weight loss or minimal gain (less than 1.2 kg). Spontaneous menses occurred in 2 girls, and 3 others were given estrogen replacement. Bone mineral density of the lumbar spine did not change significantly (mean +/- SD, 0.836 +/- 0.137 vs. 0.855 +/- 0.096 g/cm2), while whole body bone mineral density increased (0.710 +/- 0.118 vs. 0.773 +/- 0.105; P less than 0.05). Despite gains in bone mineral, 8 patients had osteopenia of the spine and/or whole body. Changes in weight, height, and BMI were significant predictors of change in bone mineral density. Increased bone mass occurred with weight gain before return of menses; conversely, weight loss was associated with further decreases in bone density. In 1 patient who failed to gain weight, estrogen therapy resulted in increased spinal, but not whole body, bone mineral. We also studied a second group of 9 women who had recovered from AN during adolescence. All 9 had normal whole body bone mineral for age, but 3 had osteopenia of the lumbar spine. We conclude that osteopenia in adolescents with AN reflects bone loss, perhaps combined with decreased bone accretion. Weight rehabilitation results in increased bone mineral before the return of menses. Estrogen may have an independent effect on bone mass. The persistence of osteopenia after recovery indicates that deficits in bone mineral acquired during adolescence may not be completely reversible.