Biochemical markers of bone remodeling: recent data of their applications in managing postmenopausal osteoporosis

The recent development of new biochemical markers has considerably improved the non invasive exploration of bone turnover. Currently, the most sensitive markers to access bone formation are osteocalcin, bone alkaline phosphatase and N-terminal propeptide of type I procollagen. Blood or urinary immunoassays of pyridinoline, deoxy-pyridinoline and terminal telopeptides type I of collagen are currently the best indices to evaluate the bone resorption. The principal application fields of biochemical markers in postmenopausal osteoporosis, in combination with the measurement of the bone mineral mass, are primarily the monitoring of anti-resorptive therapy response and prediction of bone loss and risk of fractures. In fact, treatment with anti-resorptive drugs is followed by rapid decrease of bone markers levels (3 months for the markers of resorption and 6 months for those of osteo-formation ), whereas the bone mineral density measurements requires at least two years to change significantly.     

Biomarkers of bone health and osteoporosis risk

The assay features of biochemical markers of bone turnover have markedly improved in the past few years. The most sensitive and specific markers of bone formation include serum bone alkaline phosphatase, total osteocalcin (including the intact molecule and the large N-mid fragment) and the procollagen type I N-terminal propeptide assay. Among the various markers of bone resorption, measurements of the urinary excretion of N- and C-terminal cross-linked telopeptides) and of serum C-terminal cross-linked telopeptides are the most sensitive and specific. Markers of bone turnover can be used to predict the rate of bone loss in post-menopausal women and can also be used to assess the risk of fractures. In osteoporosis-treatment studies (with alendronate, risedronate, raloxifene) markers of bone turnover appear even more strongly associated with fracture risk reduction than bone mineral density (BMD). These observations support the use of markers of bone turnover as surrogates for fracture risk reduction, perhaps even more so than BMD. Bone markers can also be used to monitor the efficacy of antiresorptive therapy such as hormone-replacement therapy, raloxifene and bisphosphonates in individual patients. Furthermore, they have also proved to be helpful in monitoring the response to nutritional interventions and have the advantage over BMD in that they provide information about mechanism of effect and changes are often observed much more rapidly.     

The interest of biochemical markers of bone turnover for monitoring treatment of postmenopausal osteoporosis

BACKGROUND: Postmenopausal osteoporosis is especially female pathology, whose incidence increases with age. AIM: The purposes of this study are to evaluate the level of bone turnover by the determination of markers of bone formation (PAL, BAP) and marker of bone resorption (CTX) in the osteoporotic women, to study the correlations between bone biochemical markers, clinical parameters and radiological measurements and to assess the interest of biochemical markers therapeutic monitoring after 6 months of antiresorptive treatment. METHODS: The authors report a prospective study of 134 osteoporotic women classified in two groups according to the presence of osteoporotic fracture. Patients of the first group G1 (n=102) with fractures, were treated by the bisphosphonates (risedronate), whereas the ones of the second group G2 (n=32) without fractures, were submited to calcic supplementation and vitamin D. RESULTS: The analyses showed that the femoral and lumbar BMD were statistically lower in the presence of osteoporotic fractures. However, the values of CTX were statistically higher in the patients of G1 group compared to those of the G2 group (0,708 +/- 0,332 ng/ml versus 0,514 +/- 0,225 ng/ml). The CTX were statistically correlated with the femoral and lumbar BMD (r = -0,21, p<0,05 and r= -0,348, p<0,001). The hypovitminosis were observed in 50,98% (52/102) of women with ostéoporotic fractures, whereas it was only 25% (8/32) in women without fractures. After 6 months of treatment by the bisphosphonates, the PAL, the BAP and the CTX have decreased with an average of, respectively, 19%, 46,5% and 62,9%. These variations were significantly more important in G1 group. CONCLUSION: The biochemical markers of bone turnover, in particular those of the resorption (CTX), can predict the postmenopausal woman's bone loss evaluated by BMD, the risk of fractures and the efficiency of the bone treatments.     

Zinc Pharmacotherapy for Elderly Osteoporotic Patients with Zinc Deficiency in a Clinical Setting

Although there have been reported associations between zinc and bone mineral density (BMD), no reports exist on the effect of zinc treatment in osteoporotic patients. Therefore, we investigated the efficacy and safety of zinc pharmacotherapy in Japanese elderly patients. The present investigation included 122 osteoporotic patients with zinc deficiency, aged ≥65 years, who completed 12 months of follow-up. In addition to standard therapy for osteoporosis in a clinical setting, the subjects received oral administration of 25 mg zinc (NOBELZIN^®, an only approved drug for zinc deficiency in Japan) twice a day. BMD and laboratory data including bone turnover markers were collected at 0 (baseline), 6, and 12 months of zinc treatment. Neither serious adverse effects nor incident fractures were seen during the observation period. Serum zinc levels were successfully elevated by zinc administration. BMD increased significantly from baseline at 6 and 12 months of zinc treatment. Percentage changes of serum zinc showed significantly positive associations with those of BMD. Bone formation markers rose markedly from the baseline values, whereas bone resorption markers displayed moderate or no characteristic changes. Additive zinc supplementation may contribute to BMD augmentation ensuing the prevention of fracture occurrence in elderly osteoporotic patients with zinc deficiency.     

Pharmacologic treatment of osteoporosis--2011

Osteoporosis affects approximately 9% of the population in Hungary resulting in about 100 000 osteoporotic fractures annually. Thirty-five percent of patients with hip fractures due to osteoporosis will die within 1 year. Direct costs of osteoporosis exceed 25 billion forints per year. Apparently, cost-effective reduction of bone loss and consequent fracture risk will add up to not only financial savings but improvement in quality of life, as well. A number of pharmacological modalities are available for this purpose. The mainstay of the treatment of osteoporosis is the bisphosphonate group that includes effective anti-resorptive compounds mitigating bone loss and fragility. The recently registered denosumab exhibits similar efficacy by neutralizing RANK ligand, however, marked differences can be observed between the two drug classes. Strontium has a unique mechanism of action by rebalancing bone turnover, and thus, providing an efficient treatment option for the not fast bone losers who are at high fracture risk. The purely anabolic teriparatide is available for the extremely severe osteoporotic patients and for those who do not respond to other types of therapy. Older treatment options such as hormone replacement therapy, raloxifene, tibolone or calcitonin may also have a restricted place in the management of osteoporosis.     

Systematic review and meta-analysis of the bone protective effect of phytoestrogens on osteoporosis in ovariectomized rats

Phytoestrogens are candidate drugs for the treatment of osteoporosis. Many experiments have been designed to investigate the preventive effects of phytoestrogens for osteoporosis; however, it is easy for a single dissenting result from animal experiments to mislead clinical investigations. Herein, we use meta-analysis to assess the evidence for a protective effect of phytoestrogens on ovariectomized rat models of osteopenia. With respect to osteoporosis, PubMed and Web of Science were searched from January 2000 to March 2013 for relevant studies of phytoestrogens in ovariectomized rats. Two reviewers independently selected and assessed the studies. Data were aggregated using a random effects model. Meta-analysis revealed that the phytoestrogen treatment group demonstrated a significantly higher femur bone mineral density and trabecular bone and lower bone turnover markers (serum alkaline phosphatase and serum osteocalcin) compared with the control ovariectomized group, thus showing a bone protective effect of phytoestrogens in ovariectomized rats. Subsequent sensitivity analyses indicated that the effect of phytoestrogens on serum alkaline phosphatase and serum osteocalcin are not robust. Despite the high heterogeneity in the systematic review of animal experiments, the present results indicated that phytoestrogens may offer the most potential for the prevention of bone loss by reducing the expected loss of trabecular bone and bone mineral density. Their effects are likely due to inhibition of bone resorption, but their benefits on bone formation are still unclear. Further studies are needed to assess the effect of phytoestrogens on bone formation and the efficacy and safety of individual phytoestrogens.     

Treating osteoporosis

The aims of treatment of established osteoporosis are the alleviation of symptoms and reduction of the risk of further fractures. Currently available drugs are used to prevent further bone loss and can reduce the risk of further fractures by up to 50%. Drugs to increase bone mass inhibit bone resorption or stimulate bone formation. Most drugs approved for use in osteoporosis inhibit bone resorption, but some of these (e.g. hormone replacement therapy (HRT), bisphosphonates) increase BMD by 5-10% over the first 2 years of treatment. However, this contribution notes that drug treatments should be monitored by BMD, because some patients fail to respond to certain drugs. There is also evidence that the rate of bone loss is accelerated once treatment is stopped; it is therefore important to measure BMD or bone turnover markers after stopping treatment.     

Effect of Korean oriental medicine extract on bone mass as compared with alendronate in ovariectomized rats

A number of alternative medicines (AMs) have often been used as traditional therapies for various diseases without scientific or clinical evidence supporting their use. The present study examined the pharmaceutical effects of an AM extract with a long history of use as a traditional medicine for various bone diseases. To evaluate it as a potential candidate for use as an anti-osteoporotic drug, we investigated the effects of the AM extract on the progression of bone loss in ovariectomized (OVX) rats fed a calcium (Ca)-deficient diet for 4 or 12 weeks. We also compared the AM extract with alendronate, an anti-resorptive drug. The AM extract did not influence bone turnover as indicated by biochemical markers [i.e., deoxypyridinoline (DPD)]. In contrast, alendronate treatment seemed to reduce bone turnover via inhibition of bone resorption as evidenced by reduced urinary DPD concentrations accompanied by a tendency for decreased serum tartrate-resistant acid phosphatase. Administration of alendronate or AM extracts did not significantly affect bone density, although both tended to increase bone mineral density (BMD) and bone strength of the femur. Although both treatments did not affect vertebral BMD and bone strength, histological analysis of vertebrae showed well-developed trabecular networking in OVX rats treated with alendronate or AM extract, in contrast to the thin and disconnected trabecule in OVX rats. In conclusion, the AM extract produced a very weak effect on the prevention of bone loss induced by OVX and Ca deficiency in rats, but was similar to the results observed with alendronate. Further verification is necessary to justify the use of the AM extract as a treatment for osteoporosis.     

Prevention and Treatment of Osteoporosis in Postmenopausal Women

Postmenopausal osteoporosis is characterized by an increased rate of bone turnover accompanied by a reduction in bone mineral density (BMD) that results in an increased risk of fracture, especially of the vertebrae, hip, or wrist. Alendronate (Fosamax®, Fosamax Once-Weekly®), an oral bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism, is a first-line therapy for the management of postmenopausal women with, or at risk of developing, osteoporosis.Alendronate produces sustained increases in BMD and reductions in bone turnover from baseline, and reduces the risk of vertebral, hip, wrist, and other fractures in women with postmenopausal osteoporosis. It also prevents bone loss, and reduces the risk of radiographic or clinical vertebral fracture in postmenopausal osteopenia. Provided administration instructions are followed, alendronate is generally well tolerated. Adverse events are usually transient and are associated with the upper gastrointestinal tract (abdominal pain, nausea, acid regurgitation, dyspepsia); moreover, the incidence of these adverse events with alendronate was similar to those with placebo. More serious events (esophagitis, gastric or duodenal ulceration or bleeding) are uncommon. Once-weekly formulations are as effective and as well tolerated as once-daily alendronate in postmenopausal women.Pharmacoeconomic evaluations suggest that alendronate is a viable treatment option in postmenopausal osteoporosis. The reduction in fracture-related healthcare utilization seen with alendronate results in decreased direct costs, including inpatient or long-term care. Markov state-transition models suggest that this could at least partially offset costs incurred with alendronate therapy. Treatment of women with osteoporosis aged 65 years and older, and postmenopausal women with a previous osteoporotic fracture, are cost-effective strategies. Alendronate is also likely to increase quality-adjusted life-years in any postmenopausal women with osteoporosis.In conclusion, clinical and economic data support the use of alendronate in postmenopausal osteoporosis. It effectively reduces bone turnover, increases BMD, and reduces the risk of osteoporotic fracture in postmenopausal women with established osteoporosis, especially older women with a higher risk of fracture. Although its cost effectiveness in postmenopausal women with osteopenia is not clearly established, alendronate is clinically effective in these patients. In addition, it is generally well tolerated when taken as recommended. Consequently, alendronate should be considered a therapy of choice in the prevention and treatment of osteoporosis in postmenopausal women.     

Markers of bone turnover: consideration on their clinical application in osteoporosis

Osteoporosis is a condition in which an imbalance appears between bone resorption and formation, with bone resorption exceeding formation. However since the rate of bone loss varies significantly from one individual to another resulting in different degrees of osteoporosis, new biochemical techniques to measure products of bone resorption and bone formation have been used in the last years allowing us to evaluate the degree of bone turnover. Bone tissue is constituted of an inorganic component and an organic matrix of collagen and noncollagenous proteins. Suitable bone marker should report the formation and degradation of all these constituents. Today markers of bone formation and markers of bone resorption are available. According to recent literature and personal data assessment of bone metabolism by the specific biochemical markers is helpful to select osteoporotic patients with high or low bone turnover and these parameters should be used to evaluate whether bone remains sensitive to different therapies.     

Fulminant Skeletal Failure in a Centenarian: The Impact of Nutrition and Immobility

This case describes a 103-year-old lady who presented from home with an incidental diagnosis of a left femoral fracture. She had no history of trauma and denied pain. She had a known diagnosis of osteoporosis, and sustained a fracture of the contralateral femur aged 93 which was managed conservatively. She was bed-bound with fixed contractures, poor oral intake and was non-compliant with prescribed calcium/vitamin D supplementation. Clinical biochemical measurements showed severe vitamin D deficiency and mild hypocalcaemia. Secondary hyperparathyroidism in the setting of an inappropriately normal phosphate suggested concurrent renal bone disease. Biomarkers of bone turnover were also consistent with bone remodelling. The history of prior fragility fractures, severe vitamin D deficiency and immobility supports a diagnosis of osteoporotic fracture, however other causes of spontaneous fracture were also considered. This case highlights the complexity of interpreting clinical biochemistry results in the setting of multi-morbidity and addresses the challenges of bone health management in the frail older person.

     

Bisphosphonate treatment prevents hip fractures in 70-79 year old women with osteoporotic vertebral fractures

According to the data of a fracture intervention trial, in women aged 55-80 years with vertebral fractures or osteoporosis diagnosed by bone mineral density measurement, treatment with the bisphosphonate alendronate prevented hip fractures with numbers-needed-to-treat within 5 years of treatment of 46 and 66, respectively. In a large risedronate hip fracture study, this new bisphosphonate only showed a beneficial effect in women aged 70-79 years with moderately severe osteoporosis as judged by femoral neck T-score, when one or more vertebral fractures were present at the start of the treatment. The number-needed-to-treat was 29. However, in women aged over 80 years and who were selected predominantly on the basis of clinical risk factors for hip fracture, no effect was found with this drug on hip fracture rate, suggesting that most were not osteoporotic and/or that the clinical risk factors used did not have the clinical utility in identifying hip fracture risk. Other factors besides osteoporosis may play a more important role in causing hip fracture in this elderly group. Diagnosis of osteoporotic vertebral fractures in women aged 70-79 years is predictive of not only new vertebral fractures but also of hip fractures, and could therefore form an indication for drug treatment.     

Glucocorticoid induced risk of fractures

In recent years studies have emphasized the importance of glucocorticoid-induced osteoporosis as the second most common form of osteoporosis after postmenopausal osteoporosis. Several studies have underlined that glucocorticoids are responsible for decreasing bone mineral density and increasing bone fragility, resulting in a large increase in fracture risk. This review wants to provide a background regarding the fracture risk of patients exposed to glucocorticoid treatment, considering the fracture risk as the most appropriate parameter to valuate glucocorticoid-induced osteoporosis. In fact, glucocorticoid treatment induces bone loss and increases fracture risk above all affecting trabecular bone, probably through an alteration in bone turnover and microarchitectural changes responsible for an early increased fracture risk which is primary influenced by dose and duration of treatment, body mass index, age and female gender.     

The Burden of Osteoporosis and the Case for Disease Management

Currently, osteoporosis, defined as low bone mineral density (BMD), affects 30% of postmenopausal women and 8% of men >50 years old in Western society and these percentages are likely to increase as our elderly population expands. Osteoporosis-related fractures increase with age and reductions in BMD, with the greatest increase in hip, followed by vertebral, and then wrist fractures. Osteoporosis is associated with significant mortality and for each 1 SD decrease in BMD there is a 1.5-fold increase in mortality risk. Following a hip fracture, 25–30% of patients will die within 3–6 months and in some populations hip fractures account for 1.5% of all deaths. Osteoporosis and related fractures are associated with significant morbidity, with loss of independence, psychological effects, and an overall decreased quality of life.The current financial cost of osteoporosis in the US is $US14 billion and in the UK just over £1 billion, and these costs will increase 3- to 8-fold over the next 50 years. Treatments are available that have been shown to significantly increase BMD, decrease bone turnover, and as a result decrease fracture incidence. For reductions in both vertebral and fracture, the evidence is strongest for the use of the bisphosphonates alendronate and risedronate; while for vertebral fracture, effective treatments include raloxifene, etidronate, calcitonin, and calcium plus vitamin D. Recent data suggest that hormone replacement therapy (HRT) can prevent hip and vertebral fractures, but long-term use, or commencement in elderly women of some continuous combined preparations, is no longer recommended.It has been recognized that bone turnover and bone quality contribute to fracture risk and, therefore, biochemical assessment of bone resorption and formation may increase the clinical and cost effectiveness of treatment. Using a conservative estimate of fracture reduction (35%) over a 5-year period, an intervention costing $US500 (£333) per year is cost effective when targeted to women with osteoporosis who are ≥65 years of age. It has been calculated that the lower the intervention cost and the higher the effectiveness of treatment the lower the age at which the treatment would be cost effective. The increasing healthcare burden and effective treatments make osteoporosis an excellent candidate for disease management programs.     

老年骨质疏松患者服用钙加维生素D后骨密度及生化指标的改变

目的了解补充钙和维生素D对骨丢失和骨转换的影响。方法对31例门诊原发性骨质疏松症和骨量减少患每日服用1片碳酸钙和维生素D复合剂(每片含元素钙600mg和维生素D125IU),连服6个月。治疗前后检测腰椎骨密度(BMD)、骨矿含量(BMC)及骨转换生化指标。结果碳酸钙和维生素D复合剂每日1片能明显改善骨质疏松引起的腰背疼和腿痛性痉挛,有明显疗效。可以维持腰椎骨密度,明显增加男性腰椎骨矿含量( 2．7％),与治疗前比较,明显提高血清250HD( 13．8％)和BGP(％29．5％),减少尿HOP／Cr比值(-17．5％)。结论老年人每天1片碳酸钙和维生素D复合剂对防止骨丢失,改善维生素D的营养状态,促进骨形成和抑制骨吸收有一定作用。     

Management of Postmenopausal Osteoporosis

Postmenopausal osteoporosis is a very common disease, and approximately half of all women aged >50 years will experience an osteoporotic fracture during the remainder of their lifetime. The predominant cause of postmenopausal osteoporosis is the decline in estrogen levels, which causes an increase in bone turnover, and results in a loss of bone mass throughout the entire skeleton. Fragility fractures, either vertebral or nonvertebral, have a considerable adverse effect on quality of life in women with osteoporosis and place a significant burden on society in terms of healthcare costs.Management of postmenopausal osteoporosis includes alteration of modifiable risk factors (e.g. lifestyle and propensity to fall), ensuring adequate calcium and vitamin D intake, and pharmacological treatment to decrease fracture risk by slowing or preventing bone loss and preserving bone strength. Raloxifene (Evista®), a selective estrogen receptor modulator that partially mimics the effects of estrogen on bone and lipid metabolism and acts as an antiestrogen in the breast and endometrium, is indicated for the prevention and treatment of postmenopausal osteoporosis. Raloxifene increases bone mineral density at vertebral and nonvertebral sites, and decreases the risk of vertebral fracture to a similar extent to the bisphosphonates alendronate and risedronate. However, effects on nonvertebral fracture risk, including the risk of hip fracture, have not been observed.Raloxifene appears to reduce breast cancer risk (in women at average risk) and cardiovascular risk (in women at increased risk) without stimulating the endometrium, and does not cause vaginal bleeding or breast pain. However, the drug causes hot flashes in some women, and increases the risk of venous thromboembolic events by about the same amount as hormone replacement therapy (HRT).In economic models, raloxifene is cost effective compared with no treatment, HRT, calcitonin, or alendronate for the prevention or treatment of postmenopausal osteoporosis.In conclusion, raloxifene is a valuable and cost-effective therapy for preventing the progression of osteoporosis and for reducing vertebral fracture risk in osteoporotic postmenopausal women. The tendency for raloxifene to cause hot flashes, and its apparent lack of effect on hip fracture risk, may preclude its use in women with vasomotor symptoms and in patients at high risk for hip fracture. Results from large ongoing trials are needed to confirm the effects of raloxifene on breast cancer and cardiovascular disease. However, the effects of raloxifene on breast cancer and cardiovascular risk without stimulating the endometrium make the drug an attractive therapy for the prevention and treatment of postmenopausal osteoporosis.     

HRT in the prevention and treatment of osteoporosis

Many short term studies have shown that various HRT regimens prevent bone loss at all skeletal sites and normalise biochemical markers at bone turnover. Most, if not all, evidence is derived from cohort and case-control studies. Of concern is the observation that past HRT users are not protected against hip fracture. More attention should be devoted in the future to the long term use of a low-dose combined continuous HRT regimen in late post-menopausal women in order to reduce the burden of osteoporotic fractures.     

Statins, bone formation and osteoporosis: hope or hype?

Osteoporosis is a major health problem affecting both men and women. Statins, besides their action as lipid-lowering agents, seem to have additional pleiotropic properties, among them a beneficial effect on bone mineral density. The entirety of experimental and the majority of clinical studies as well as the only relevant meta-analysis suggest that statins have an anabolic effect on bone metabolism. Statins, osteoporosis and adipogenesis share the same pathway, RANKL/OPG. It would appear that an imbalance in this pathway could be responsible for the manifestation of some metabolic disorders such as diabetes mellitus, atherogenesis, multiple myeloma, osteoporosis. Possibly in the future, drugs which can intervene in this biochemical and pathophysiological cascade, like statins, in a variety of doses, could be used for the management of ectopic ossification syndromes and other bone disorders, even as an additive treatment. Until then, further large longitudinal randomized controlled studies for each statin separately are required to confirm this hypothesis.     

Possibilities of non-hormonal drug treatment of osteoporosis]

In many countries osteoporosis is the most common metabolic bone diseases. A great deal is known about the pathophysiology and the treatment of the disease. There is a lot of treatment possibilities and many new treatments are being tested. Therapeutic agents for osteoporosis are correspondingly classified as substances primarily inhibiting bone turnover (most of them are inhibitors of bone resorption as well) and agents that appear capable of restoring bone mass previously lost (stimulators of bone formation). From a didactic point of view the distinction of these to groups is generally accepted, but pharmacologically there is a considerable overlap between two. In this review the authors evaluate non-hormonal drugs, which are being used widely in the treatment of osteoporosis. The key points of the evaluation are the mechanism of action, the effects on bone mass, bone strength and fracture.     

Dried plums improve indices of bone formation in postmenopausal women

Menopause drastically increases the risk of osteoporosis. Aside from drug therapy, lifestyle and nutritional factors play an important role in the maintenance of skeletal health. Our recent findings suggest that dried plums, a rich source of phenolic and flavonoid compounds, are highly effective in modulating bone mass in an ovarian hormone-deficient rat model of osteoporosis. The objective of this study was to examine whether the addition of dried plums to the diets of postmenopausal women positively influences markers of bone turnover. Fifty-eight postmenopausal women not on hormone replacement therapy (HRT) were randomly assigned to consume either 100 g dried plums or 75 g dried apples daily for 3 months. Both dried fruit regimens provided similar amount of calories, fat, carbohydrate, and fiber. Serum and urinary biochemical markers of bone status were assessed before and after treatment. In comparison with corresponding baseline values, only dried plums significantly increased serum levels of insulin-like growth factor-I (IGF-I) and bone-specific alkaline phosphatase (BSAP) activity. Higher levels of both serum IGF-I and BSAP are associated with greater rates of bone formation. Serum and urinary markers of bone resorption, however, were not affected by either dietary regimen. The results of this study suggest that dried plums may exert positive effects on bone in postmenopausal women. Longer duration studies are needed to confirm the beneficial effects of dried plum on bone mineral density (BMD) and the skeletal health of postmenopausal women.