Zoledronate.

Zoledronate is the most potent and most long-acting bisphosphonate in clinical use, and is administered as an intravenous infusion. Its major uses are in osteoporosis, Paget's disease, and in myeloma and cancers to reduce adverse skeletal related events (SREs). In benign disease, it is a first- or second-line treatment for osteoporosis, achieving anti-fracture efficacy comparable to that of the RANKL blocker, denosumab, over 3 years, and it reduces fracture risk in osteopenic older women. It is the preferred treatment for Paget's disease, achieving higher rates of remissions which are much more prolonged than with any other agent. Some trials have suggested that it reduces mortality, cardiovascular disease and cancer, but these findings are not consistent across all studies. It is nephrotoxic, so should not be given to those with significant renal impairment, and, like other potent anti-resorptive agents, can cause hypocalcemia in patients with severe vitamin D deficiency, which should be corrected before administration. Its most common adverse effect is the acute phase response, seen in 30-40% of patients after their first dose, and much less commonly subsequently. Clinical trials in osteoporosis have not demonstrated increases in osteonecrosis of the jaw or in atypical femoral fractures. Observational databases are currently inadequate to determine whether these problems are increased in zoledronate users. Now available as a generic, zoledronate is a cost-effective agent for fracture prevention and for management of Paget's disease, but wider provision of infusion facilities is important to increase patient access. There is a need to further explore its potential for reducing cancer, cardiovascular disease and mortality, since these effects could be substantially more important than its skeletal actions.

Biochemical assessment of Paget's disease of bone.

Biochemical measurements of bone turnover provide an objective assessment of disease activity and the response to treatment. Alkaline phosphatase is the best characterized of the bone turnover markers and reflects the extent and activity of Paget's disease. However, in addition to bone-specific alkaline phosphatase (Bone ALP), there is also osteocalcin (OC) and procollagen type 1 N-terminal propeptide (P1NP) as formation markers. A variety of telopeptides (C-terminal telopeptide of type I collagen, [CTX], N-telopeptide of type I collagen [NTX]) or cross-link breakdown products of type 1 collagen can be used to assess bone resorption. Total alkaline phosphatase (Total ALP), Bone ALP, and P1NP all perform similarly in diagnosis and in evaluating the response to treatment, but the general availability, low interassay variation, and inexpensiveness of Total ALP makes it the best test for routine use. Measurement of the biological variability of the different markers in stable, untreated Paget's disease indicates how great a change (critical difference) is needed to define a true alteration in disease activity. Bone ALP, P1NP, and NTX show the highest therapy induced change/critical difference ratio during antiresorptive treatment. Some of the resorption markers show more complex changes in response to treatment. Pyridinoline (PYD) or deoxypyridinoline (DPD) cross-links of type 1 collagen are excreted in urine either as free or as peptide bound moieties, but it is the latter which decrease by the greatest amount in response to bisphosphonate therapy. Newly formed type 1 collagen contains an aspartyl-glycine motif (alphaCTX), which undergoes spontaneous isoaspartyl formation to betaCTX as the bone ages. In untreated Paget's disease, the alphaCTX is raised proportionately more (16-fold) than betaCTX (3-fold) and decreases in response to bisphosphonate therapy to a greater extent than betaCTX (measured in the sCTX assay). As bisphosphonates have become more potent, the aim of treatment has shifted toward the achievement of a rate of bone turnover in the lower part of the reference range. This is important because the duration of remission of disease activity is strongly determined by the post treatment nadir bone turnover.

Vertebral morphometry by DXA: a comparison of supine lateral and decubitus lateral densitometers.

Identification of vertebral fracture has become increasingly important in the diagnosis and management of osteoporosis. This study compares the morphometric techniques on a fan beam dual-energy X-ray absorptiometry (DXA) GE-Lunar Expert system (Expert) using a supine lateral position and a narrow fan beam GE-Lunar Prodigy system (Prodigy; GE Lunar, Madison, WI) that requires lateral decubitus positioning. Patient acceptability, image quality, observer, and equipment variability were determined. Study subjects were recruited from clinical referrals sent for a routine DXA study that included vertebral morphometry. Twenty-five patients underwent lateral vertebral assessment on both machines and completed a questionnaire on comfort and tolerability. Analysis was undertaken by two trained observers. Vertebral height, anterior/posterior height (A/P) and mid/posterior height (M/P) ratios, image quality, and prevalent fractures were assessed. There were no significant differences in patient comfort or image quality scores. More upper thoracic vertebrae could be assessed on the Expert, and good radiographic positioning was easier to achieve on the Expert. Inter-observer coefficients of variance percentage (CV%) of vertebral height was lower on the Prodigy (3.5% in the lumbar spine rising to 12.8% in the thoracic spine) than the Expert (4.2% to 16.9%). Inter-observer CV% for A/P and M/P ratios varied from 2.5% to 10.5% on the Prodigy compared with 3.5% to 12.3% on the Expert, depending on vertebral level. The variation between instruments was similar to the inter-observer CV% (anterior height: -0.11+/-1.65 mm; mid height: 0.54+/-1.51 mm; posterior height: 0.43+/-1.46 mm). There was good agreement between observers and between the Expert and Prodigy in identifying severe fractures, but lack of agreement in identifying moderate fractures. In conclusion, there was no clinically significant difference in patient comfort and image quality between the Expert and the Prodigy. The inter-observer variations in vertebral height and A/P and M/P ratios are similar to the variations between instruments. In making the change from the supine lateral to the decubitus lateral positioning, measurements of vertebral height are reproducible and patient comfort is not compromised.

Prevention of postmenopausal bone loss: six-year results from the Early Postmenopausal Intervention Cohort Study.

We report the effect of continuous treatment with alendronate for 6 yr vs. placebo in the Early Postmenopausal Intervention Cohort study. A total of 1609 healthy, early postmenopausal women were recruited; we describe results for the 585 women who received continuous placebo or alendronate (2.5 or 5 mg) daily for 6 yr. Bone mineral density (BMD) was evaluated at the lumbar spine, hip, forearm, and total body at baseline and annually thereafter. Bone turnover markers were measured every 6 months from baseline to yr 2 and annually thereafter. Adverse experiences, including upper gastrointestinal events and fractures, were recorded throughout the study. Women receiving placebo experienced progressive decreases in BMD at all skeletal sites. Patients receiving alendronate experienced significant gains in spine and hip BMD that were maintained through yr 6. Significantly greater, dose-related decreases in bone turnover markers in the alendronate groups vs. placebo occurred within the first year and were sustained through yr 6. Women receiving alendronate had adverse experience incidences similar to those receiving placebo. Fractures occurred in 11.5, 10.3, and 8.9% of women taking placebo, 2.5 mg alendronate, or 5 mg alendronate daily, respectively. Therapy with alendronate is an effective and promising strategy for the prevention of postmenopausal osteoporosis.

Biochemical measurements in the prediction of histologic subtype of renal transplant bone disease in women.

Renal transplant osteodystrophy encompasses several histologic subtypes. Bone histomorphometric examination reliably distinguishes these groups but is invasive, is time-consuming, and delays diagnosis. Establishing a noninvasive method of correctly predicting histologic subtype in an individual to direct management is an attractive proposition. We identified 19 female renal transplant recipients with histologic evidence of hyperparathyroid bone disease (HPTH) and 14 with adynamic bone (ADB). We evaluated serum osteocalcin and bone-specific alkaline phosphatase as bone formation markers and urinary hydroxyproline (Hypro) and deoxypyridinoline cross-links as bone resorption markers. Mean concentrations for all markers were higher in the HPTH group, reaching significance for Hypro (HPTH, 24.8 +/- 4.2 micromol/mmol creatinine; ADB, 13.2 +/- 5.0 micromol/mmol creatinine; P = 0.01). A cutoff of 16.4 micromol/mmol creatinine for Hypro (Youden's index, 0.65) gave a sensitivity of 93% and specificity and positive predictive value (PPV) of 72% in predicting HPTH. In combination, Hypro greater than 16.4 micromol/mmol creatinine and parathyroid hormone greater than 80 pg/mL gave a specificity of 100%, sensitivity of 32%, and PPV of 100%. Conversely, for predicting ADB, Hypro less than 15.1 micromol/mmol creatinine (Youden's index, 0.45) gave a specificity of 93%, sensitivity of 53%, and PPV of 91%. Hypro less than 15.1 micromol/mmol creatinine plus osteocalcin less than 6.8 microg/L gave a specificity of 84.2%, sensitivity of 64.3%, and PPV of 75%. Significant associations between markers and histomorphometry were evident only for Hypro and osteocalcin (with osteoblast surface) and all markers (except deoxypyridinoline cross-links) with cortical volume. Markers have limited utility in identifying histologic subtype (Hypro was most effective) and, with the exception of Hypro and osteocalcin, showed little association with cell surface markers of bone cell activity.

Changes in bone density and turnover after alendronate or estrogen withdrawal.

OBJECTIVE: To compare bone mineral density (BMD) and bone turnover changes after therapy withdrawal in postmenopausal women treated with alendronate or estrogen-progestin. DESIGN: In this randomized, blinded, multinational, placebo-controlled trial, 1,609 healthy postmenopausal women ages 45 to 59 years were assigned to receive alendronate, placebo, or open-label estrogen-progestin (conjugated equine estrogens plus medroxyprogesterone acetate or a cyclic regimen of 17 beta-estradiol, norethisterone acetate and estradiol). Of the original women, one third after year 2 and one third after year 4 were switched from alendronate to placebo, while remaining blinded to treatment assignment. The women taking estrogen-progestin in years 1 to 4 were followed off therapy in years 5 and 6. BMD at the lumbar spine and hip and biochemical markers of bone turnover were measured. RESULTS: The treatment groups described in the current report represent 860 women at baseline; 481 women entered year 5, and 430 completed 6 years. BMD steadily decreased in the placebo group during all 6 years. In contrast, spine and hip BMD increased during the first 4 years in the groups receiving daily continuous alendronate 5 mg and estrogen-progestin. During years 5 and 6, BMD decreased at the lumbar spine -2.42% (95% CI = -4.10, -0.74) and total hip -1.09% (-2.60, 0.41) in the group previously treated with alendronate 5 mg for 4 years. In comparison, large BMD decreases were observed at the spine [-7.69% (-8.96, -6.41)] and total hip [-5.16% (-6.30, -4.01)] among women who had received estrogen-progestin for 4 years. CONCLUSION: Alendronate produces greater residual skeletal effects than estrogen-progestin after therapy discontinuation.

Changes in serum markers of bone turnover during normal pregnancy.

BACKGROUND: Maternal calcium homeostasis adapts during pregnancy to provide for the needs of the growing fetal skeleton. Wide selections of bone turnover markers are currently available to assess the changes taking place; here, data are presented on two serum-based markers. METHODS: The use of serum-based biochemical bone turnover markers during pregnancy was assessed in a cohort of 41 women recruited prior to conception. Serum N-terminal extension peptide of procollagen (P1NP) was used to monitor bone formation and serum beta-crosslaps (S-CTX) used to assess resorption. Blood samples were measured at five time points from a pre-conceptual baseline, through pregnancy, to the final sample, which was taken within 1 week of delivery. RESULTS: An initial decrease from the baseline in both P1NP and S-CTX was observed at 12 weeks; however, it is suggested that this may be due to the haemodilutional effect of pregnancy rather than a true change in bone turnover. Significant increases from the baseline of both analytes were observed by 36 weeks (P1NP, P = 0.013; S-CTX, P = 0.002), when the calcium demands of the fetus are greatest. CONCLUSIONS: This study illustrates the use of serum-based bone turnover markers to assess turnover during normal pregnancy, a time when ionizing radiation cannot be used to assess bone turnover.

Longitudinal changes of insulin-like growth factors and their binding proteins throughout normal pregnancy.

BACKGROUND: Insulin-like growth factors (IGFs) are anabolic proteins that are essential regulators of cell division, differentiation and growth. We describe the longitudinal changes in IGF-I, IGF-II and the binding proteins IGFBP-1, -2 and -3 before and during normal pregnancy. METHOD: Serum samples were taken before conception and then at 12, 24 and 36 weeks of gestation in 41 healthy women with uncomplicated pregnancies. We measured IGF-I using an automated chemiluminescent method, IGF-II and IGFBP-2 using in-house radioimmunoassays (RIAs), and IGFBP-1 and IGFBP-3 using commercial enzyme-linked immunosorbent assay (ELISA) and RIA kits, respectively. Because of the potential haemodilution effects during pregnancy, albumin was also measured in all samples. RESULTS: There was a significant fall in IGF-I during the first (36%) and second trimesters (21%) followed by an increase of 25% at 36 weeks. During pregnancy, the mean IGF-II concentrations fell by 12% at 12 weeks, 8% at 24 and 8% at 36 weeks compared with pre-conception values. When IGF-II results were adjusted for the haemodilution of pregnancy, its concentrations increased. During pregnancy, there was a rapid increase in mean IGFBP-1 levels by 17-fold (12 weeks), 24-fold (24 weeks) and 25-fold (36 weeks). IGFBP-2 concentrations fell after conception but started to increase towards term. This increase was more significant when adjusted for haemodilution. In contrast, IGFBP-3 concentrations increased significantly throughout pregnancy. CONCLUSION: Our data on the physiological changes of IGFs and their binding proteins add further evidence of the vital roles of these hormones throughout normal pregnancy.

Comparison of intact and 'whole molecule' parathyroid hormone assays in patients with histologically confirmed post-renal transplant osteodystrophy.

BACKGROUND: Fragments of parathyroid hormone (PTH) have been identified (amino acids 7-84) which may interfere with commercially available 'intact molecule' PTH assays. Novel assays which employ an antibody directed to the first seven amino acids of the N-terminus of PTH are thought to be free from cross-reactivity with the 7-84 fragments, and therefore measure true 'whole molecule' PTH. Transplant recipients (as well as those in end-stage renal failure) have been reported to have elevated levels of 'intact' in comparison with 'whole molecule' PTH. METHODS: PTH concentrations were assessed in serum samples obtained from female renal transplant recipients previously classified as either having hyperparathyroid (n = 14) or adynamic bone disease (n = 14) by transiliac crest bone biopsy. PTH was measured as 'whole molecule' (Scantibodies 'whole molecule' PTH) and 'intact' (DPC Immulite 2000 intact PTH and Scantibodies total PTH). RESULTS: Scantibodies 'whole molecule' PTH (all-subject mean 48.7 ng/L, +/- 53.0) were significantly lower than DPC intact (83.5 ng/L, +/- 88.1; P < or = 0.0001) and Scantibodies total PTH (80.5 ng/L, +/- 92.4; P < or = 0.0001). However, the differences between the 'whole molecule' and 'intact' measurements were similar across the two patient groups, and reflected the lower reference range employed by the 'whole molecule' assay. CONCLUSION: The 'whole molecule' PTH assay was unable to discriminate between the two patient populations and provided very little additional clinical information to that obtained from the intact PTH assays.

Paget's disease of bone: an endocrine society clinical practice guideline.

OBJECTIVE: The aim of this guideline was to formulate practice guidelines for the diagnosis and treatment of Paget's disease of the bone. PARTICIPANTS: The guideline was developed by an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence. CONCLUSIONS: We recommend that plain radiographs be obtained of the pertinent regions of the skeleton in patients with suspected Paget's disease. If the diagnosis is confirmed, we suggest that a radionucleotide bone scan be done to determine the extent of the disease. After diagnosis of Paget's disease, we recommend measurement of serum total alkaline phosphatase or, when warranted, a more specific marker of bone formation or bone resorption to assess the response to treatment or evolution of the disease in untreated patients. We suggest treatment with a bisphosphonate for most patients with active Paget's disease who are at risk for future complications. We suggest a single 5-mg dose of iv zoledronate as the treatment of choice in patients who have no contraindication. In patients with monostotic disease who have a normal serum total alkaline phosphatase, we suggest that a specific marker of bone formation and bone resorption be measured, although these may still be normal. Serial radionuclide bone scans may determine the response to treatment if the markers are normal. We suggest that bisphosphonate treatment may be effective in preventing or slowing the progress of hearing loss and osteoarthritis in joints adjacent to Paget's disease and may reverse paraplegia associated with spinal Paget's disease. We suggest treatment with a bisphosphonate before surgery on pagetic bone.

Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect.

The selective cathepsin K inhibitor odanacatib (ODN) progressively increased bone mineral density (BMD) and decreased bone-resorption markers during 2 years of treatment in postmenopausal women with low BMD. A 1-year extension study further assessed ODN efficacy and safety and the effects of discontinuing therapy. In the base study, postmenopausal women with BMD T-scores between -2.0 and -3.5 at the lumbar spine or femur received placebo or ODN 3, 10, 25, or 50 mg weekly. After 2 years, patients (n = 189) were rerandomized to ODN 50 mg weekly or placebo for an additional year. Endpoints included BMD at the lumbar spine (primary), total hip, and hip subregions; levels of bone turnover markers; and safety assessments. Continued treatment with 50 mg of ODN for 3 years produced significant increases from baseline and from year 2 in BMD at the spine (7.9% and 2.3%) and total hip (5.8% and 2.4%). Urine cross-linked N-telopeptide of type I collagen (NTx) remained suppressed at year 3 (-50.5%), but bone-specific alkaline phosphatase (BSAP) was relatively unchanged from baseline. Treatment discontinuation resulted in bone loss at all sites, but BMD remained at or above baseline. After ODN discontinuation at month 24, bone turnover markers increased transiently above baseline, but this increase largely resolved by month 36. There were similar overall adverse-event rates in both treatment groups. It is concluded that 3 years of ODN treatment resulted in progressive increases in BMD and was generally well tolerated. Bone-resorption markers remained suppressed, whereas bone-formation markers returned to near baseline. ODN effects were reversible: bone resorption increased transiently and BMD decreased following treatment discontinuation.

A single infusion of zoledronic acid produces sustained remissions in Paget disease: data to 6.5 years.

Two trials have shown that a single 5-mg infusion of zoledronic acid achieves much higher response rates in Paget disease of bone than risedronate. The duration of this effect is unknown. We have conducted an open follow-up of responders from the two trials (152 originally treated with zoledronic acid, 115 with risedronate) out to 6.5 years without further intervention. Endpoints were times to relapse (ie, return of serum total alkaline phosphatase activity to within 20% of the pretreatment value) or loss of response (response = normalization of alkaline phosphatase or 75% or greater reduction in its excess). Bone turnover markers were lower in the zoledronic acid group throughout follow-up, with mean alkaline phosphatase (ALP) remaining within the reference range in these patients, whereas the mean in the risedronate group was above normal from 1 year. Relapse rates were substantially greater in the risedronate group (23 of 115, 20%) than in those treated with zoledronic acid (1 of 152, 0.7%, p < .001), and loss of response occurred in 19 (12.5%) zoledronic acid patients compared with 71 (62%) risedronate patients (p < .0001). Risk ratios for relapse and loss of response in zoledronic acid patients were 0.02 [95% confidence interval (CI) 0.00-0.18] and 0.12 (95% CI 0.07-0.19), respectively. Changes from baseline in quality of life, assessed using SF-36 scores, were more positive in the zoledronic acid group across the follow-up period (p = .01). Bone markers at 6 months were predictive of response duration. These data demonstrate an unprecedented duration of remission of Paget disease following treatment with zoledronic acid, accompanied by an improved quality of life.

Relationship between vitamin D status, parathyroid hormone levels and bone mineral density in patients with chronic kidney disease stages 3 and 4.

AIM: Low vitamin D status is associated with secondary hyperparathyroidism and increased bone turnover in the general population and can aggravate the hyperparathyroidism of chronic kidney disease (CKD) patients. It is also correlated to low bone mineral density (BMD), but this correlation is less clear in CKD patients. Aims of our study were to investigate these associations in CKD stages 3 and 4 patients, and to identify significant predictors of BMD in this population. METHODS: Serum 25-hydroxyvitamin D (25OHD) levels, BMD at the femur and radius, and bone mineral metabolism parameters were measured in 89 CKD stages 3 and 4 patients. Vitamin D status was defined according to the NKF/KDOQI guidelines. RESULTS: Mean 25OHD levels were 53.8+/-32.1 nmol/L and correlated to the severity of proteinuria. Thirty-five patients (39%) had vitamin D insufficiency, 29 (33%) had vitamin D deficiency and five (6%) had severe deficiency. Of the 89 patients, two had osteoporosis and 31 had osteopenia either at femur or radius. Independent predictors for the total femur BMD were the intact parathyroid hormone (iPTH) levels and the body mass index (BMI). For the total radius BMD, independent predictor was only the BMI. Serum 25OHD levels were not directly associated with BMD, but they were independent predictors of iPTH. CONCLUSION: Vitamin D insufficiency and deficiency are very common in CKD stages 3 and 4 population and may indirectly affect, via effects on iPTH, the BMD of these patients.

Oral antiresorptive therapy.

Oral antiresorptive agents play a pivotal role in the management of osteoporosis. This paper discusses the effects and potential future role of newer agents such as ibandronate. Alternative dosing schedules and routes of administration have become available and may improve fracture protection, compliance, and tolerability for the long term treatment of a chronic condition such as osteoporosis. Increasingly these agents are being used to reduce bone loss in other diseases associated with high risk for osteoporosis such as organ transplantation and cystic fibrosis. Such studies may act as prototypes for the extended use of this class of drugs in other chronic inflammatory disease states. The innovative, yet disappointing results from combining an antiresorptive agent (alendronate) with the anabolic effects of teriparatide is also discussed. The major problem that remains is the lack of direct comparison between the agents in terms of fracture endpoints.

Reduced bone mineral density in male renal transplant recipients: evidence for persisting hyperparathyroidism.

BACKGROUND: Osteoporosis is increasingly recognized as a major source of morbidity following renal transplantation. The aim of this cross-sectional study was to determine the prevalence of osteoporosis in a cohort of male transplant recipients and examine factors that may influence their bone loss. METHODS: Bone mineral density (BMD) and biochemical markers of bone metabolism were measured in 134 out of 154 male renal allograft recipients in our center. RESULTS: The mean age of the patients was 49.7 years (range 26-76) with a median of 6 years post-transplant. Only 17% had normal BMD, 30% were osteoporotic at either hip or spine, and this proportion rose to 41% if the ultradistal radius was included. Parathyroid hormone (PTH) was negatively correlated with BMD at all skeletal sites. In a multiple regression model, independent predictors of femoral neck BMD included body mass index (p=0.004), diabetes (p=0.025), and PTH (p=0.049). The only independent predictor of BMD at the ultradistal radius was PTH (p<0.001). Nineteen men sustained a total of 25 appendicular fractures after transplantation (median time to fracture was 3 years). Prevalent vertebral fractures were only identified in five men. PTH was elevated in 72.4% of patients (mean PTH 142 +/- 118 pg/ml). Bone resorption markers were increased in 48% of patients. PTH was positively correlated with serum carboxyterminal telopeptide of type 1 collagen (r=0.473, p<0.001) and procollagen type 1 amino terminal propeptide (r=0.419, p<0.001). CONCLUSIONS: Osteopenia and osteoporosis are common in male transplant recipients, and the hip and radius are the most severely affected sites. Elevated rates of bone resorption driven by hyperparathyroidism appear to be the most important contributing factor.

Oral antiresorptive therapy.

Oral antiresorptive agents play a pivotal role in the management of osteoporosis. This paper discusses the effects and potential future role of newer agents such as ibandronate. Alternative dosing schedules and routes of administration have become available and may improve fracture protection, compliance, and tolerability for the long term treatment of a chronic condition such as osteoporosis. Increasingly these agents are being used to reduce bone loss in other diseases associated with high risk for osteoporosis such as organ transplantation and cystic fibrosis. Such studies may act as prototypes for the extended use of this class of drugs in other chronic inflammatory disease states. The innovative, yet disappointing results from combining an antiresorptive agent (alendronate) with the anabolic effects of teriparatide is also discussed. The major problem that remains is the lack of direct comparison between the agents in terms of fracture endpoints.

Rescue of trophoblast apoptosis by parathyroid hormone-related protein.

The effects of the 1-34 N-terminal parathyroid hormone-related protein fragment (0-10 microM) and the 67-86 parathyroid hormone-related protein fragment (0-10 microM) on trophoblast apoptosis, induced by TNFalpha and IFN-gamma or by the protein kinase inhibitor staurosporine, were investigated. TNFalpha/IFN-gamma and staurosporine significantly increased the rate of apoptosis by fivefold and by eightfold, respectively. Parathyroid hormone-related protein (1-34) evoked a dose-dependent rescue of both TNFalpha/IFNgamma-induced and staurosporine-induced apoptosis, whereas parathyroid hormone-related protein (67-86) had no significant effect on staurosporine-induced apoptosis, and only significantly diminished TNFalpha/IFNgamma-induced apoptosis at 10 microM. Parathyroid hormone-related protein was thus found to be a cytotrophoblast apoptosis survival factor.