Biochemical Markers Of Bone Resorption Research Articles

Role of Vitamin D and Parathyroid Hormone in the Regulation of Bone Turnover and Bone Mass in Men: The MINOS Study

We investigated the role of vitamin D and of parathyroid hormone (PTH) in the regulation of bone mineral density (BMD), tone dimensions and seasonal variation of bone turnover in 881 men aged 19-85 years. Bone mineral content (BMC) and BMD of the lumbar spine, hip and whole body were measured with HOLOGIC 1000W and those of distal forearm with an OSTEOMETER DTX 100 device. Bone formation was evaluated using osteocalcin, bone alkaline phosphatase and N-terminal extension propeptide of type I collagen (PINP). Bone resorption was evaluated by 24-hour excretion of deoxypyridinoline and of C-terminal telopeptide of collagen type I. In young men (< 55 yrs) PTH level decreased with age (r = -0.18, P < 0.005) whereas 25-hydroxyvitamin D (25OHD) concentration was stable. In older men (> 55 years) 25OHD decreased whereas PTH increased with age (r = -0.27 and r = 0.21, P = 0.0001). In young men, 25OHD level varied with season but not PTH, biochemical markers of bone turnover nor BMD. In young men, 25OHD, but not PTH, was a significant determinant of BMC, cortical thickness and of biomechanical properties of the femoral neck. Biochemical bone markers and BMD were not correlated with PTH nor with 25OHD. In elderly men, winter levels of 25OHD were lowest whereas those of PTH, bone resorption markers and PINP were highest. After adjustment for age, body weight and season, biochemical markers of bone turnover were correlated with PTH. In elderly men, 25OHD and PTH were significant determinants of BMC, cortical thickness and of biomechanical parameters of the femoral neck. Men with vertebral deformities had lower concentrations of 25OHD, higher PTH levels and slightly elevated urinary excretion of biochemical markers of bone resorption compared with men without vertebral deformities. In conclusion, in young men, 25OHD discloses a seasonal variability in contrast to PTH and biochemical bone markers. In this group, 25OHD is a significant determinant of BMC and BMD but not of bone size. In elderly men, seasonal variation of 25OHD and PTH concentrations result in seasonal variation of bone resorption. In this group, both 25OHD and PTH are determinants of BMC and cortical thickness of the femoral neck and, consequently, of its mechanical parameters.

Novel approaches to the management of bone metastases

Standard management of breast cancer metastatic to bone includes systemic chemotherapy and, if applicable, hormone therapy, as well as radiotherapy for control of pain or prevention of pathologic fractures. In addition, orthopedic surgical procedures are used to prevent or correct pathologic fractures in weight-bearing areas of the osseous skeleton. Inhibitors of osteoclast function, including bisphosphonates and gallium nitrate, have been shown in clinical trials to decrease bone-related complications. Consequently, bisphosphonates have become an integral part of the management of bone metastases from breast cancer. Improved understanding of the biology of osteoclastogenesis led to the identification of osteoprotegerin as a critical modulator of osteoclast activity. The clinical evaluation of several osteoprotegerin preparations has shown therapeutic effects as measured by significant reductions in biochemical markers of bone resorption. Monoclonal antibodies to RANK ligand and parathyroid hormone-related protein, as well as Src kinase inhibitors, are also currently under clinical evaluation.

Increased bone resorption and failure to respond to antiresorptive therapy in progressive dystrophic calcification.

The aim of this study was to evaluate strategies to halt the progression of severe dystrophic calcification in a patient with progressive systemic sclerosis (PSS) and to monitor serial changes in biochemical markers of bone resorption and indices of calcium (Ca) metabolism in response to therapy. The relationship of bone turnover to the extent of dystrophic calcification was also investigated in a number of additional patients with varying degrees of calcinosis. Serial markers of bone turnover and indices of Ca metabolism were measured over a 3-year period in one patient with PSS and severe dystrophic calcification. Bone mineral density (BMD) was assessed by dual-energy x-ray absorptiometry (DXA). Bone turnover in this patient and two additional patients with PSS or dermatomyositis (DM) and severe dystrophic calcification (Group A, n = 3) was compared with that in patients with connective tissue disease with little or no evidence of dystrophic calcification (Group B, n = 13). Serial data on one patient with severe progressive calcinosis showed increased bone resorption markers, which remained high over a 3-year period despite antiresorptive therapy. BMD was low. Patients with PSS/DM with severe dystrophic calcification had higher bone resorption than those with minimal or no evidence of calcification. Mean serum ionized Ca and urinary Ca excretion were both lower in those with severe calcinosis. Bone resorption was increased in patients with connective tissue disease and severe dystrophic calcification. Several antiresorptive agents were shown to be ineffective in limiting either bone turnover or clinical progression in one patient.

A Toxicity Profile of Osteoprotegerin in the Cynomolgus Monkey

Osteoprotegerin (OPG) is a novel secreted glycoprotein of the tumor necrosis factor (TNF) receptor superfamily that acts as an antiresorptive agent inhibiting osteoclast maturation. OPG acts by competitively inhibiting the association of the OPG ligand with the RANK receptor on osteoclasts and osteoclast precursors. This inhibition of osteoclasts can lead to excess accumulation of newly synthesized bone and cartilage in vivo. The purpose of this study was to investigate the potential toxicity of a human recombinant form of OPG in the young cynomolgus monkey. OPG was administered by intravenous (IV) or subcutaneous (SC) injection three times per week for either 4 or 13 weeks. There were no deaths during the study, no clinical signs related to treatment, no effect on body weight, appetence, or ophthalmology. No toxicologically relevant changes in routine laboratory investigations, organ weights, or gross or histopathological findings were observed. Serum ionized calcium and phosphorus were decreased at all dose levels. Evaluations were performed to monitor biochemical markers of bone resorption (N-telopeptide [NTx], deoxypyridinoline [DPD]), bone formation (skeletal alkaline phosphatase [s ALP], osteocalcin [OC]), parathyroid hormone [PTH], and bone density of the proximal tibia and distal radius in vivo. Dose-related decreases in NTx and/or DPD were observed at each dose level, with up to a 90% decrease in NTx noted for animals treated IV or SC at 15 mg/kg. Similar decreases were observed for s ALP and OC. PTH was increased for animals treated at 5 and 15 mg/kg (IV or SC). Trabecular bone density was increased for the majority of males and females treated IV or SC at 15 mg/kg and males treated IV at 5 mg/kg. Microscopic examination of the sternebrae revealed corresponding increases in bone. Decreases in markers of bone turnover, and corresponding increases in bone density, were consistent with the pharmacological action of OPG as an osteoclast inhibitor. The no-observable-adverse-effect level (NOAEL) of OPG was 15 mg/kg.

A toxicity profile of osteoprotegerin in the cynomolgus monkey.

Osteoprotegerin (OPG) is a novel secreted glycoprotein of the tumor necrosis factor (TNF) receptor superfamily that acts as an antiresorptive agent inhibiting osteoclast maturation. OPG acts by competitively inhibiting the association of the OPG ligand with the RANK receptor on osteoclasts and osteoclast precursors. This inhibition of osteoclasts can lead to excess accumulation of newly synthesized bone and cartilage in vivo. The purpose of this study was to investigate the potential toxicity of a human recombinant form of OPG in the young cynomolgus monkey. OPG was administered by intravenous (i.v.) or subcutaneous (s.c.) injection three times per week for either 4 or 13 weeks. There were no deaths during the study, no clinical signs related to treatment, no effect on body weight, appetence, or ophthalmology. No toxicologically relevant changes in routine laboratory investigations, organ weights, or gross or histopathological findings were observed. Serum ionized calcium and phosphorus were decreased at all dose levels. Evaluations were performed to monitor biochemical markers of bone resorption (N-telopeptide [NTx], deoxypyridinoline [DPD]), bone formation (skeletal alkaline phosphatase [sALP], osteocalcin [OC]), parathyroid hormone [PTH], and bone density of the proximal tibia and distal radius in vivo. Dose-related decreases in NTx and/or DPD were observed at each dose level, with up to a 90% decrease in NTx noted for animals treated i.v. or s.c. at 15 mg/kg. Similar decreases were observed for sALP and OC. PTH was increased for animals treated at 5 and 15 mg/kg (i.v. or s.c.). Trabecular bone density was increased for the majority of males and females treated i.v. or s.c. at 15 mg/kg and males treated i.v. at 5 mg/kg. Microscopic examination of the sternebrae revealed corresponding increases in bone. Decreases in markers of bone turnover, and corresponding increases in bone density, were consistent with the pharmacological action of OPG as an osteoclast inhibitor. The no-observable-adverse-effect level (NOAEL) of OPG was 15 mg/kg.

Osteoprotegerin and its correlations with new markers of bone formation and bone resorption in kidney transplant recipients

Osteopro tegerin (OPG), a natural decoy receptor for osteoclast differentiation factor, is produced by osteoblasts in response to PTH. OPG and its ligand RANKL constitute a complex mediator system involved in the regulation of bone resorption, probably playing an important role in the homeostasis of bone turnover. At present, little is known about the effects of OPG on uremic bone. Successful kidney transplantation reverses many abnormalities of bone metabolism; however, the improvement is often incomplete. The aim of the study was to assess OPG and RANKL concentrations in long-term kidney allograft recipients and their correlations with biochemical markers of bone resorption and formation. The present studies on 48 kidney transplant recipients and 25 healthy volunteers included concentrations of parathormone, osteocalcin, bone-specific alkaline phosphatase, serum CrossLaps, calcidiol, calcitriol, ICTP, PICP, tartrate-resistant acid phosphatase, β2 microglobulin, IGF-1, IFGBP-1, IGFBP-3, OPG, and RANKL using commercially available kits for measurements. Among kidney transplant recipients OPG and RANKL did not differ between transplant patients and healthy volunteers, whereas other markers of bone formation and resorption were significantly higher in the former group. OPD was related to age, time on dialysis prior transplantation, urea, platelet count, CSA dose, azathioprine dose, 25(OH)D 3, TRAP, IGF-1, IGFBP-3, whereas RANKL was related to leukocyte count, CSA concentration and dose, urine DPD, and β2 microglobulin content. In healthy volunteers OPG correlated only with CrossLaps, whereas RANKL correlated only with osteocalcin and TRAP. Correlations between OPG, IGF system components, and some markers of bone metabolism may indicate the role of OPG/RANKL system in the pathogenesis of bone metabolism disturbances following renal transplantation.

Ultralow-Dose Micronized 17β-Estradiol and Bone Density and Bone Metabolism in Older Women

Estrogen therapy is known to prevent osteoporosis, but studies have shown that conventional doses increase adverse events. Whether lower doses, one quarter of standard treatment, prevent bone loss is not known. To examine the effect of 3 years of treatment with 0.25 mg/d of micronized 17beta-estradiol on bone mineral density (BMD) and bone turnover in healthy older postmenopausal women. Randomized, double-blind, placebo-controlled trial conducted from July 24, 1998, through June 14, 2002, at a university general clinical research center in the United States. Healthy, community-dwelling women (N = 167) who were older than 65 years at enrollment. Dosage of 0.25 mg/d of micronized 17beta-estradiol (n = 83) or placebo (n = 84); all women who had not had a hysterectomy received 100 mg/d of oral micronized progesterone for 2-week periods every 6 months. The BMD of the hip, spine, wrist, and total body measured annually for 3 years. Serum and urine biochemical markers of bone resorption and formation and sex hormones were measured at baseline, 3 months, and during years 1 and 3 of treatment. Mean BMD increased at all sites for participants taking low-dose estrogen (17beta-estradiol) compared with placebo (P<.001). Compared with participants receiving placebo, participants taking low-dose estrogen had BMD increases of 2.6% for the femoral neck; 3.6%, total hip; 2.8%, spine; and 1.2%, total body. Markers of bone turnover, N-telopeptides of type 1 collagen, and bone alkaline phosphatase decreased significantly (P<.001) in participants taking low-dose estrogen compared with placebo. Estradiol, estrone, and sex hormone-binding globulin levels increased in the estrogen-treated group compared with placebo. The adverse effect profile was similar; specifically, there were no statistically significant differences in breast tenderness, changes in endometrial thickness or pathological effects, or annual mammographic results between the 2 groups. The number of abnormal mammograms over 3 years was 15 for the low-dose estrogen group and 10 for the placebo group (8 occurred at baseline) (P =.26). There were no reports of breast cancer during the study. In older women, a dosage of 0.25 mg/d of 17beta-estradiol increased bone density of the hip, spine, and total body, and reduced bone turnover, with minimal adverse effects. Future studies evaluating the effect of low-dose estrogen on fractures are indicated.

Bone metabolism in ochronotic patients.

We investigated skeletal involvement in five male and two female patients with ochronosis, aged 26-82 years. The main parameters of mineral metabolism, together with biochemical markers of bone resorption (urinary N-telopeptides of type I collagen) and formation (serum bone isoenzyme of alkaline phosphatase and serum osteocalcin) were evaluated. In the same subjects lumbar spine and femoral bone mineral density (BMD) were also measured by dual energy X-ray absorptiometry. All patients but the younger 26-year-old patient had lower than normal bone mass at femoral neck and total hip, showing marked osteopenia in three cases and osteoporosis in the remaining three cases. However, at lumbar spine BMD measurement provided spuriously overestimated results, because of intervertebral disc calcification and osteophyte formation. As far as biochemical markers of bone turnover are concerned, the most relevant finding was the increased N-telopeptides of type I collagen urinary excretion. Our results suggest that ochronosis may be associated with increased bone resorption rate leading to an accelerated bone loss. A role of the homogentisic acid polymer deposit in bone matrix and cells, possibly with osteocyte damage and interference in collagen metabolism, might be hypothesized.

Effect of Cyclical Intravenous Clodronate Therapy on Bone Mineral Density and Markers of Bone Turnover in Patients Receiving Home Parenteral Nutrition

Background: Patients receiving home parenteral nutrition (HPN) because of intestinal failure are at high risk of developing osteoporosis. Objective: We studied the effect of the bisphosphonate clodronate on bone mineral density (BMD) and markers of bone turnover in HPN patients. Design: A 12‐mo, double‐blind, randomized, placebo‐controlled trial was conducted to study the effect of 1500 mg clodronate, given intravenously every 3 mo for 1 y, in 20 HPN patients with a bone mass T score of the hip or lumbar spine of less than −1. The main outcome measure was the difference in the mean percentage change in the BMD of the lumbar spine measured by dual‐energy X‐ray absorptiometry. Secondary outcome measures included changes in the BMD of the hip, forearm, and total body and biochemical markers of bone turnover, ie, serum osteocalcin, urinary pyridinoline, and urinary deoxypyridinoline. Results: The mean (±SEM) BMD of the lumbar spine increased by 0.8 ± 2.0% in the clodronate group and decreased by 1.6 ± 2.0% in the placebo group (P = 0.43). At all secondary skeletal sites (ie, hip, total body, and distal forearm), we observed no changes or small increases in the BMD of the clodronate group. In the clodronate group, biochemical markers of bone resorption decreased significantly (P &lt; 0.05). Conclusions: Clodronate significantly inhibits bone resorption as assessed by changes in biochemical markers of bone turnover. Although the mean BMD increased in the clodronate group, cyclic clodronate therapy failed to increase spinal BMD significantly at 12 mo.

Reversible lipidization for the oral delivery of salmon calcitonin

Salmon calcitonin (sCT), a 32-amino-acid polypeptide, was lipidized by using a reversible aqueous lipidization (REAL) technology. When injected subcutaneously into mice, the AUC of REAL–sCT was four times greater than that of sCT and a similar pattern of reduction in plasma calcium level was observed. The therapeutic effect of REAL–sCT was evaluated in ovariectomized (OVX) rats. The development of osteoporosis in OVX rats was determined by measuring the urinary level of deoxypyridinoline (DPD), a biochemical marker of bone resorption. It was found that the DPD levels were significantly reduced in rats that were orally administered a dose of 50 μg/kg/day of REAL–sCT. No reduction in urinary DPD levels could be detected in OVX rats treated similarly with unmodified sCT. In addition, significant levels of sCT were detected in rat plasma up to 12 h after oral administration of REAL–sCT at 500 μg/kg, while the plasma concentration of sCT was undetectable at 1 h after oral administration with the same dose of sCT. The AUC of oral REAL–sCT was at least 19 times higher than that of sCT. Our results indicate that reversibly lipidized polypeptides exhibit not only improved pharmacokinetic and pharmacodynamic behaviors, but also an enhanced oral bioavailability.

Serum leptin levels, bone mineral density and osteoblast alkaline phosphatase activity in elderly men and women

Although primarily secreted by adipose cells, leptin, a polypeptide hormone that influences body weight, satiety and lipid metabolism, and its receptor are also expressed in human osteoblasts. Leptin plays a role in the central, hypothalamic modulation of bone formation, as well as locally within the skeleton by enhancing differentiation of bone marrow stroma into osteoblasts and inhibiting its differentiation into osteoclasts and adipocytes. The purpose of this investigation was to compare serum leptin values in 100 postmenopausal women (age 62–97) and 31 men (age 72–92) to bone mineral density (BMD) measurements made by dual X-ray absorptiometry and additionally to biochemical markers of bone resorption and formation, including crosslinked collagen N-telopeptides (NTx), aminoterminal extension procollagen propeptides (PINP) and bone-specific alkaline phosphatase (bAP). The circulating level of leptin directly correlated with body mass index (BMI) ( r=0.61–0.78, P<0.001) and was modestly, but significantly and positively associated with bAP activity ( r=0.24–0.33, P<0.01) in the sera of men and women after adjustment for BMD, age and BMI. The association of circulating leptin levels with bAP, a specific marker of osteoblast activity suggests that leptin levels influence osteoblast activity in vivo in elderly women and men.

Secondary Osteoporosis in Liver Transplant Recipients: a Longitudinal Study in Patients With and Without Cholestatic Liver Disease

Background: Metabolic bone disease is one of the major long-term complications in liver transplant recipients, but it remains unclear which patients are at highest risk for developing severe bone disease following transplantation. Methods: A total of 46 consecutive, adult patients with chronic liver disease accepted for a liver transplantation waiting list were prospectively included in the study. The patients were classified into two groups: group A—chronic cholestatic liver disease (n = 28), and group B—chronic non-cholestatic liver disease (n = 18). Bone mineral density (BMD) was measured at acceptance for the waiting list and at 3, 12 and 36 months following transplantation. Markers of bone turnover (serum-bone specific alkaline phosphatases (bALP), s-osteocalcin, s-l-collagen-C-terminal telopeptide (1-CTP) and urine N-terminal telopeptides u-Ntx) were measured at acceptance and at 3, 6, 12, 24 and 36 months following transplantation. BMD and markers of bone turnover were compared with similar values in a matched control group of 42 healthy individuals. Results: BMD decreased significantly during the early post-transplantation period (median bone loss femoral neck (FN) 3 months post-transplant 8.5%). BMD levels declined slightly from 3 to 12 months following transplantation and increased thereafter. The relative bone loss was greatest among group B patients (relative bone loss FN 3 months post-transplant: group A, 8% versus group B, 13%; P = 0.04). At 36 months, 8/17 group A and 2/9 group B patients had BMD levels that exceeded the pretransplant levels (P = 0.12). The early bone loss was positively correlated with an increase in resorption markers (s-1-CTP and u-Ntx). Group B had higher levels of both s-1-CTP and u-Ntx at 3 and 6 months post-transplant than group A patients (P = 0.03). Bone formation markers increased slowly from 6 months post-transplant and onwards. Relative bone loss was positively correlated to total glucocorticoid dose during the first 3 months post-transplant. There were no differences in BMD between patients receiving tacrolimus versus those receiving'cyclosporin A. Conclusion: Bone loss following liver transplantation is considerable in patients with both cholestatic and non-cholestatic liver disease, the first group has the poorest starting-point while the latter group has the greatest bone loss following transplantation. Bone loss is closely correlated with biochemical markers of bone resorption and total dose of glucocorticoids given post-transplant.

Mediators of periodontal osseous destruction and remodeling: principles and implications for diagnosis and therapy.

Osteoclastic bone resorption is a prominent feature of periodontal disease. Bone resorption via osteoclasts and bone formation via osteoblasts are coupled, and their dysregulation is associated with numerous diseases of the skeletal system. Recent developments in the area of mediators of osteoclastic differentiation have expanded our knowledge of the process of resorption and set the stage for new diagnostic and therapeutic modalities to treat situations of localized bone loss as in periodontal disease. This review describes the current state of knowledge of osteoclast differentiation and activity, mediators, and biochemical markers of bone resorption and their use and potential use in clinical periodontics. Finally, therapeutic strategies based on knowledge gained in the treatment of metabolic bone diseases and in periodontal clinical trials are discussed, and the potential for future strategies is proposed relative to their biologic basis. The intent is to update the field of periodontics on the current state of pathophysiology of the osteoclastic lesion and outline diagnostic and therapeutic strategies with a rational basis in the underlying biology.

Clinical review 151: The role of parathyroid hormone in the pathogenesis of glucocorticoid-induced osteoporosis: a re-examination of the evidence.

One of the most important of the secondary causes of osteoporosis is chronic exposure to glucocorticoids, which are used for an extraordinarily large number of disorders. The adverse effects of hypercortisolism on bone metabolism were recognized more than half a century ago (1). Today, glucocorticoid exposure in the context of medicinal use has become far more common than excess endogenous exposure (Cushing’s syndrome). Glucocorticoid-induced osteoporosis (GIO) is the third most common cause of osteoporosis, trailing only postmenopausal and age-related osteoporosis (2). As many as 50% of individuals on chronic glucocorticoid therapy will suffer an osteoporotic fracture (3). Recently, a large-scale retrospective cohort study by Van Staa et al. (4) in England clearly demonstrated that fracture risk is increased across virtually the entire dosage range of oral glucocorticoids. A large number of subjects with a history of glucocorticoid exposure (n 244,235) were matched to the same number of control patients who had no history of glucocorticoid exposure. The average age of the subjects was 57 yr; respiratory diseases were the common indication for therapy, being prescribed in 40% of the patients (4). Referent to nonglucocorticoid users, subjects with a history of glucocorticoid therapy had significantly greater risk for fractures at the spine (rr 2.6), the hip (rr 1.6), and at any nonvertebral site (rr 1.3). The magnitude of the fracture risk was directly related to dosage, with subjects receiving as little as 2.5 mg of prednisolone at significantly greater risk than control subjects (4). Bone loss from glucocorticoid use was also found to occur rapidly, within the first 3 months of treatment. A similarly precipitous loss of bone mass has also been observed prospectively when glucocorticoids are used in the setting of organ transplantation (5, 6), and in other clinical situations (7–10). Even inhaled steroids have been implicated as a cause of bone loss (11, 12). The cardinal feature of GIO on skeletal dynamics is a reduction in bone formation. Bone formation is inhibited, in part, through a decrease in osteoblast life span and function. Histomorphometric studies demonstrate a marked reduction in indices of bone formation, such as reduced mineral apposition rate and prolonged mineralization lag time. The amount of bone that is replaced in each remodeling cycle can be reduced by as much as 30% (13–17). Biochemical markers of bone formation, osteocalcin and bone-specific alkaline phosphatase, are suppressed. In addition to this primary suppressive effect on bone formation, glucocorticoids also induce an early phase of accelerated bone resorption (18). Osteoclast number and activity increase, along with an increase in the fraction of eroded bone surface (14, 15). Biochemical markers of bone resorption, urinary N-telopeptide and pyridinoline cross-link excretion, rise during early glucocorticoid exposure (17, 19, 20). This early phase of glucocorticoid use, therefore, can be associated with rapid bone loss due to both reduced bone formation and accelerated bone resorption. With continued use of glucocorticoids, the rapid rate of osteoclast-mediated bone resorption slows (14), but suppression of bone formation continues as the dominant skeletal dynamic. Thus, bone loss is progressive because bone resorption chronically exceeds bone formation. Although bone loss due to glucocorticoid use tends to be diffuse, the axial skeleton is targeted preferentially. The cancellous bones of the vertebral spine are typically affected, whereas cortical bone sites of the appendicular skeleton (i.e. forearm) are affected to a lesser extent (21, 22). Spontaneous fractures of the vertebrae or ribs are common complications of GIO (23).

Does active treatment of rheumatoid arthritis limit disease-associated bone loss?

Generalized bone loss in rheumatoid arthritis (RA) is multi-factorial, with the inflammatory disease itself thought to contribute to bone loss. To study the extent to which control of disease activity affects bone turnover in RA and whether treatment with disease-modifying anti-rheumatic drugs (DMARDs) reduces bone turnover and loss of bone mass, we measured bone density and biochemical markers of bone resorption in a group of patients with active RA starting on DMARDS. Patients with active RA were enrolled on starting a new DMARD. Patients were mobile and none took steroids or any treatment for osteoporosis. Clinical and laboratory measures of disease activity were made at 3-monthly intervals and an index of disease activity (DAS) calculated. Bone density was assessed at 0, 1 and 2 yr (Hologic QDR 4500c). Urinary deoxypyridinoline (D-PYR) and pyridinoline (PYR) were measured by ELISA at 0, 3, 6, 9 and 12 months. Forty patients were enrolled, mean age 59.5 (range 31-76), 26 female, 14 male, 25 had established RA, 15 had RA for <2 yr. Baseline D-PYR was elevated (8.4+/-4.55 nmol/mmol creatinine) and correlated with ESR (r=0.6, P<0.01) and DAS (r=0.4, P<0.05). On treatment ESR and DAS fell by 38.5 and 29.3%, respectively. D-PYR was reduced by 12.3% by 9 months (P<0.01). Spearman rank order correlation showed ESR to be the most significant determinant of D-PYR over 1 yr (r=0.43, P<0.001). Serial bone density was available on 21 patients. There was no significant change in BMD over the 2 yr. The change in DAS over 0-3 months showed an inverse relationship with the percent change in spine over 1 yr (r=-0.5, P=0.05). The change in D-PYR over 0-3 months was not closely related to the change in BMD at hip or spine at 1 yr. Disease activity is a significant determinant of bone turnover in RA. Bone resorption markers fall on treatment of RA with DMARDs and no change in BMD was demonstrated at 2 yr. This study suggests the need to control disease activity in RA in order to prevent systemic bone loss.

Effect of cyclical intravenous clodronate therapy on bone mineral density and markers of bone turnover in patients receiving home parenteral nutrition

Patients receiving home parenteral nutrition (HPN) because of intestinal failure are at high risk of developing osteoporosis. We studied the effect of the bisphosphonate clodronate on bone mineral density (BMD) and markers of bone turnover in HPN patients. A 12-mo, double-blind, randomized, placebo-controlled trial was conducted to study the effect of 1500 mg clodronate, given intravenously every 3 mo for 1 y, in 20 HPN patients with a bone mass T score of the hip or lumbar spine of less than -1. The main outcome measure was the difference in the mean percentage change in the BMD of the lumbar spine measured by dual-energy X-ray absorptiometry. Secondary outcome measures included changes in the BMD of the hip, forearm, and total body and biochemical markers of bone turnover, ie, serum osteocalcin, urinary pyridinoline, and urinary deoxypyridinoline. The mean (+/-SEM) BMD of the lumbar spine increased by 0.8 +/- 2.0% in the clodronate group and decreased by 1.6 +/- 2.0% in the placebo group (P = 0.43). At all secondary skeletal sites (ie, hip, total body, and distal forearm), we observed no changes or small increases in the BMD of the clodronate group and decreases in the BMD of the placebo group. In the clodronate group, biochemical markers of bone resorption decreased significantly (P < 0.05). Clodronate significantly inhibits bone resorption as assessed by changes in biochemical markers of bone turnover. Although the mean BMD increased in the clodronate group, cyclic clodronate therapy failed to increase spinal BMD significantly at 12 mo.

Calcium in mineral water can effectively suppress parathyroid function and bone resorption

The present study was designed to measure the effects, on parathyroid function and bone metabolism, of ingestion of high-calcium mineral water and of a calcium salt bringing the same dose (600 mg) of calcium as a reference. Fifteen healthy young men (mean ± SD age : 23.3 ± 1.2) ingested, during 3 different experimental periods chosen at random, a) high-calcium mineral water (596 mg/L), b) low-calcium mineral water as a control assay, c) one bag of tricalcium phosphate powder containing 600 mg of calcium. Serum concentrations of ionized calcium (iCa), intact parathyroid hormone (iPTH) and of a biochemical marker of bone resorption, type I collagen cross-linked C telopeptide (CTX), were measured before 08.00 and every hour from 09.00 to 17.00. Serum iCa concentrations were significantly ( P < 0.0001) higher and serum iPTH concentrations were significantly ( P < 0.01) lower after oral intake of both high-calcium water and tricalcium phosphate than in control period. Serum concentrations of CTX were significantly lower after either high-calcium water ( P < 0.0001) or tricalcium phosphate ( P = 0.011) than in the control period and a statistically significant difference ( P < 0.05) using Bonferroni t test between the effects of high-calcium mineral water and of tricalcium phosphate was observed from 14.00 to 17.00. The same total amount of calcium (# 600 mg) from one liter of high-calcium mineral water, divided into three intakes, at 3 hours intervals, resulted in a more prolonged suppression of serum CTX, than from the ingestion of a calcium salt.

The clinical use of bone resorption markers in patients with malignant bone disease.

Advanced tumors often metastasize to bone, resulting in a variety of skeletal complications. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption that reduce the incidence and delay the onset of skeletal complications and reduce the need for radiation and surgery. Biochemical markers of bone resorption have been identified that can augment the imaging techniques used to diagnose bone metastases and assess response to bisphosphonate therapy. In the current study, the available literature regarding bone resorption markers is reviewed and the clinical relevance of these data with respect to the treatment of bone metastases discussed. Urinary calcium and hydroxyproline have been widely used to assess bone metabolism, but do not appear to be well correlated with clinical outcome in patients with bone metastases. Several unique breakdown products of Type I collagen (including pyridinium crosslinks, pyridinoline, and deoxypyridinoline) and peptide-bound crosslinks (N-telopeptide and C-telopeptide) are more specific and sensitive markers of bone resorption. N-telopeptide and C-telopeptide have been identified as the most sensitive biochemical markers currently available for detecting bone metastases and for assessing response to therapy or disease progression. To the author's knowledge markers of bone resorption have not yet been recommended for routine clinical use. However, further research is needed to define their potential role in the diagnosis of bone metastases, the assessment of disease progression and response to bisphosphonate therapy, and predict the rate of bone loss and the potential for fracture. Suppression of bone resorption markers in response to bisphosphonate therapy appears to correlate with clinical outcome in patients with both osteolytic and blastic bone lesions; therefore, the goal of bisphosphonate therapy should be to suppress markers of bone resorption.

Comparison of the Humoral Markers of Bone Turnover and Bone Mineral Density in Patients on Haemodialysis and Continuous Ambulatory Peritoneal Dialysis

Renal osteodystrophy is an important complication in patients with end-stage renal disease on maintenance dialysis. The aim of this study was to compare the biochemical markers of bone formation (serum collagen type I C-terminal propeptide) and resorption (serum deoxypyridinoline – DPD – and pyridinoline – PYR) with the bone mineral density (BMD) at lumbar spine, femoral neck, and forearm in patients with end-stage renal disease on haemodialysis (HD) versus continuous ambulatory peritoneal dialysis (CAPD). Fifty-nine adult patients, 45 on CAPD (18 females, 27 males) and 14 on HD (2 females, 12 males), were studied. The mean age was 44 ± SEM 1.6 and 54.4 ± 4.8 years, respectively. No significant differences in serum calcium, phosphorus, creatinine, and parathyroid hormone were found between patients on HD and CAPD in predialysis samples. Serum urea was significantly lower (p = 0.02) in the CAPD group. Serum PYR (nmol/l) and DPD (nmol/l) were significantly higher in patients on HD as compared with those on CAPD: 105 ± 23.3 versus 43.7 ± 3.47 (p = 0.007) and 31.0 ± 2.4 versus 24.4 ± 1.4 (p = 0.027), respectively. The results were still significantly higher in the HD patients following correction for serum creatinine and body mass index. There was a close correlation between dialysate DPD and creatinine in both dialysis modalities (HD r = 0.9, CAPD r = 0.76). The clearance of DPD did not differ significantly between the CAPD membrane and the HD membrane (p = 0.22). Serum collagen type I C-terminal propeptide was not significantly different between the HD and CAPD patients. The results were unaffected following correction for age and gender. The BMD was measured in 38 (65%) of the patients (HD n = 8, CAPD n = 30) by dual-energy X-ray absorptiometry and expressed as ‘Z’ scores. This was reduced at all sites in the patients with end-stage renal disease. The BMD was significantly lower at the ultradistal forearm (mostly trabecular bone) in HD patients as compared with CAPD patients (n = 0.02). A similar trend was observed at the lumbar spine, although the results failed to reach significance. In the whole population (n = 38), linear regression analysis revealed a significant negative correlation between BMD at the ultradistal forearm and serum PYR (r = –0.35, p = 0.04) and DPD (r = –0.33, p = 0.049). Combined measurements of BMD and biochemical markers of bone resorption may have potential in the identification of patients at high risk of bone loss who may require further evaluation of bone remodeling by bone histomorphometry.

Clinical and biochemical determinants of bone metabolism and bone mass in adolescent female patients with anorexia nervosa.

Among pathologies prevalent in western societies, anorexia nervosa has increased over the last decade. Its effects on bone mass need to be defined, and prognostic factors, either clinical or biochemical, could aid clinicians in individual patient management. To determine which clinical and/or biochemical parameters could be related to bone mass status in adolescent female anorexia nervosa patients, 73 female patients were classified according to different stages of their illness and studied in terms of clinical and biochemical parameters and bone densitometric mineral content at lumbar spine. Patients (age 17.2 +/- 1.7 y, mean +/- SD) with Tanner pubertal stage 5, regular menstruation for more than 3 mo before the onset of secondary amenorrhea, and diagnosed with anorexia nervosa were consecutively studied and classified in three clinical situations: I) active phase (34 patients): undernourished and amenorrheic; II) weight recovered but still amenorrheic (20 patients); III) fully recovered (19 patients). Clinical data were recorded at the time of bone density measurement, concomitant with blood sample extraction for study of IGF-I, IGF-binding protein 3 (IGFBP-3), IGFBP-1, estradiol, sex hormone-binding globulin, dehydroepiandrosterone sulfate, prealbumin, amino-terminal propeptide of procollagen III, osteocalcin, bone alkaline phosphatase, carboxy-terminal propeptide of procollagen I, amino-terminal propeptide of procollagen I, carboxy-terminal telopeptide of collagen I, 25-OH-vitamin D, 1,25(OH)(2)-vitamin D, and parathormone. In addition, a 24-h urine collection was made for cortisol, GH, deoxypyridinoline, amino-terminal telopeptide of collagen I, and calcium and creatinine content analysis. IGF-I, estradiol, and biochemical bone formation markers were higher and IGFBP-1, sex hormone-binding globulin, and biochemical bone resorption markers were lower in the weight-recovered stages (stages II and III) compared with the active phase (stage I). Bone formation markers correlated positively with body mass index SD score and IGF-I, whereas bone resorption markers correlated negatively with body mass index SD score and estradiol. Although no statistically significant differences regarding lumbar spine bone mineral density SD score values were recorded among the three stages of the illness, the proportion of osteopenic patients was clearly lower among stage III patients. The actual bone mineral density was inversely related to the duration of amenorrhea and directly related to duration of postmenarcheal menses before amenorrhea. In addition, a subset of osteopenic patients (five of 19) in the fully clinically recovered group with accelerated bone turnover was identified. Normal circulating estrogen level exposure time predicts actual bone mineral density at lumbar spine in young adolescent anorexia nervosa patients. In addition to psychiatric and nutritional interventions, estrogen-deprivation periods must be shortened to less than 20 mo. Patients remaining osteopenic at full clinical recovery require additional follow-up studies.