Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover.

INTRODUCTION: Teriparatide is a bone formation agent that increases bone turnover and mass, resulting in an increase in bone strength and a decrease in fracture risk. METHODS: The primary purpose of this analysis was to evaluate the association between pretreatment bone turnover marker (BTM) concentrations and the absolute and relative fracture risks after adjusting for baseline femoral neck BMD, number of prevalent vertebral fractures, and age. Because femoral neck BMD is commonly attained in the assessment of patients at risk for osteoporosis, we examined the ability of a multivariate assessment including pretreatment BTM concentration and femoral neck BMD to predict future fracture risk after adjusting for the number of prevalent vertebral fractures. We examined data from the Fracture Prevention Trial, a study designed to determine the effect of teriparatide 20 mcg/day and teriparatide 40 mcg/day on vertebral and nonvertebral fracture risk in postmenopausal women with osteoporosis. BTM were analyzed in two subsets of women within the Fracture Prevention Trial, and included serum bone-specific alkaline phosphatase (BSAP), serum carboxy-terminal extension peptide of procollagen type I (PICP), serum amino-terminal extension peptide of procollagen type I (PINP), urinary free deoxypyridinoline (DPD), and urinary N-terminal telopeptide (NTX). RESULTS: Teriparatide significantly reduced the risk of fracture [four BTM subset (n = 520), placebo = 14.3%, teriparatide = 5.8%, P < 0.05; PINP subset (n = 771), placebo = 17.7%, teriparatide = 5.5%, P < 0.05]. Subjects with the highest pretreatment BTM concentrations had the greatest fracture risk. Teriparatide-mediated absolute risk reduction was greatest for women with high pretreatment bone turnover; however, the relative fracture risk reduction was independent of pretreatment bone turnover. After adjusting for pretreatment BTM and number of prevalent vertebral fractures, baseline femoral neck BMD was not a significant predictor of fracture risk. CONCLUSION: Teriparatide-mediated relative fracture risk reduction was independent of pretreatment bone turnover, demonstrating that this therapy offers clinical benefit to patients across a range of disease severity.

Effects of prostaglandin E1 on the metabolism in rat parathyroid gland in vitro.

We investigated some effects of prostaglandin E1 on the metabolism of rat parathyroid glands using a culture system containing basal Eagle's medium supplemented with 5--10% heat-inactivated rat serum. Rat parathyroid glands incorporate [3H]fucose and 14C-labeled amino acids into cellular glycoproteins and secrete some of these into the culture medium. Gel filtration chromatography separates these glycoproteins into three classes, the smallest of which (peak 3) is secreted with immunoreactive parathyroid hormone. In cultures of 48 h, prostaglandin E1 (1 microgram/ml) specifically inhibits the secretion of peak 3 and of parathyroid hormone but has no effect on the incorporation of [3H]fucose, 14C-labeled amino acids, or [3H]uridine into parathyroid glands. Cytochalasin B inhibits the secretion of parathyroid hormone and the incorporation of isotopic fucose and amino acids. Cortisol stimulates incorporation of [3H]fucose and the secretion of parathyroid hormone even in the presence of inhibitory doses of prostaglandin E1. It is concluded that, in organ culture, prostaglandin E1 inhibits the secretion of parathyroid hormone and of a specific glycoprotein the function of which may be related to the secretion of the hormone.

Symmetrical bone scan in a patient with acute hypercalcemia.

A previously healthy 49-year-old woman had symptoms of acute hypercalcemia that was not parathyroid-hormone mediated. Despite no clinical signs or symptoms of arthritis, a bone scan showed increased uptake in the juxtaarticular areas of the joints in the upper and lower extremities. The biopsy specimen of skeletal lesions noted on roentgenograms supported a diagnosis of multiple myeloma. Symmetrical lesions on bone scan in a patient with asymptomatic joints and acute hypercalcemia may be the first sign of an underlying hematologic malignant neoplasm.

Dose-response relationships for alendronate treatment in osteoporotic elderly women. Alendronate Elderly Osteoporosis Study Centers.

Alendronate (ALN) is an aminobisphosphonate employed as an antiresorptive agent in the treatment of osteoporosis. The present study was carried out to determine dose-response relationships, particularly the effects of relatively low doses of ALN, on bone mineral density (BMD), biochemical indexes of bone and mineral metabolism, and bone histology, with particular attention to effects in elderly women. This prospective, randomized, double blind, 2-yr multicenter study compared the effects of placebo with those of 1.0, 2.5, or 5.0 mg ALN daily. All subjects received supplemental calcium (500 mg daily) as the carbonate. We studied 359 women with lumbar spine BMD at least 2.0 SD below the peak young adult mean. Subjects were stratified by age, with 135 aged 60-69 yr and 224 aged 70-85 yr. Histomorphometry was performed on transiliac bone biopsies obtained from 104 subjects after 1 yr and from 83 subjects after 2 yr. This study elucidated the previously uninvestigated lower region of the dose-response curve for ALN in osteoporosis. Over 2 yr, treatment with 1.0, 2.5, or 5.0 mg/day increased lumbar spine BMD, on the average, by 0.65%, 3.54%, and 5.67%, respectively, compared with that in the placebo group (P < 0.001 vs. placebo for the 2.5 and 5 mg groups). Significant dose-related increases were also seen in BMD at appendicular sites and in total body BMD. Dose-dependent reductions in bone turnover to new steady states were indicated by serum and urine biochemical markers as well as by histomorphometry. There was also a dose-related reduction in the proportion of subjects suffering nonvertebral fractures (P < 0.05). Safety profiles were similar for the ALN and placebo groups and for both age strata. Efficacy was similar for both age strata. There was no evidence of impaired mineralization or other histological abnormalities due to ALN treatment. We conclude that treatment with ALN over a period of 2 yr was well tolerated and produced dose-dependent increases in BMD without evidence of a plateau over the dose range of 1.0-5.0 mg daily. One milligram daily did not result in a significant effect on BMD, and 5.0 mg daily produced favorable effects at all sites measured. Other studies have demonstrated somewhat greater effects on 10 mg daily. ALN, was equally effective and well tolerated in osteoporotic women over 70 yr old as in younger women with the same condition.

Acute effects of increased meat protein on urinary electrolytes and cyclic adenosine monophosphate and serum parathyroid hormone.

The effect of a high meat protein diet on urinary electrolytes, cyclic AMP, and serum immunoassayable parathyroid hormone was studied in six subjects fed a high meat protein diet (1.5 to 2.9 g/kg) for 7 days. The diet produced minor decreases in serum calcium and phosphorus but increased endogenous creatinine clearance by about 20% (p less than 0.02) and urinary calcium by about 80% (p less than 0.01) without changing urinary sodium. Urinary calcium correlated (p less than 0.01) with urinary sulfate (r = 0.60), ammonia (r = 0.72), and nitrogen (r = 0.60). Urinary cyclic AMP increased (p less than 0.01) 14% while serum parathyroid hormone (measured by C-terminal assays) decreased (p less than 0.05) by more than 30%. It was concluded 1) that this diet acutely altered renal handling of calcium at a site different from that of sodium, 2) that the excretion of acidic products of protein metabolism contributed to these changes, and 3) that parathyroid hormone secretion was not changed acutely.

Adverse effects of liquid protein fast on the handling of magnesium, calcium and phosphorus.

We have studied the effect of a vitamin- and potassium-supplemented liquid protein fast on mineral metabolism of six obese subjects (five women, 1 man) for 40 days. Each patient was admitted to a metabolic ward and was given daily 300 Kcal, 75 mg of calcium, 406 mg of phosphorus, 7 mg of magnesium, 33 meq of potassium, and 11.5 g of nitrogen. Urinary calcium, phosphorus and magnesium levels were greatest during the first week, but decreased as the fast continued to 21, 31 and 300 percent, respectively, above intake. Cumulative urinary losses of calcium, phosphorus and magnesium were 58, 75 and 500 percent greater, respectively, than the cumulative intake. Fecal losses for calcium, phosphorus and magnesium were less than urinary losses throughout the study. Cumulative fecal losses of magnesium were more than 30 percent greater than dietary intake. Mean daily balances were -104 mg (calcium), -48 mg (magnesium) and -363 mg (phosphorus). Serum phosphorus and magnesium levels did not change. However, serum calcium levels decreased (-0.5 mg/dl, p less than 0.05). Serum bicarbonate levels decreased 20 percent during the first 8 days of the fast, at which time urinary ammonium was maximal, but later returned to control values despite sustained increases in serum and urinary acids throughout the fast. Ammonium excretion was 260 to 300 percent above control values. Urinary titratable acid excretion was greatest early in the fast but subsequently decreased as the excretion of phosphorus declined. Titratable acid accounted for less of the excreted acid (7 to 21 percent) than did ammonia (70 to 90 percent). It is concluded that a liquid protein fast results in negative mineral balance that is not reflected by serum values and is due primarily to renal losses. The losses of magnesium were proportionally greater than those of calcium and phosphorus. These studies indicate that a liquid protein fast results in depletion of the intracellular and/or skeletal stores of these minerals.

Gorham's syndrome: a case report and review of the literature.

Gorham's syndrome is a rare disorder involving a proliferation of vascular channels associated with extensive loss of bony matrix. A case report is presented with a review of the 97 previously reported cases. The age of patients at presentation has ranged from less than one to 75 years (mean: 27 years). Sixty-four percent have been men. Fifty-seven percent have had a history of prior trauma. Laboratory values for systemic measures have usually been normal. The disease usually arrests spontaneously, but this is unpredictable. Sixteen patients (16 percent) have died of the disorder, with 10 deaths due to chest wall involvement, three to spinal cord transection, two to sepsis, and one to asphyxia and aspiration. Although the mechanism of bone loss is unknown, osteoclasts were focally increased in the case described herein. Further information and investigation are needed to better understand this unusual disorder.

Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded therapy followed by one year of open therapy.

PURPOSE: To determine the effect of long-term intermittent cyclic etidronate treatment on spinal bone density and vertebral fracture rates. PATIENTS AND METHODS: Postmenopausal osteoporotic women (n = 423) were randomized initially into a 2-year, double-blind, multicenter study; it was extended to a third year of blinded treatment followed by open-label treatment: 357 patients continued treatment in Year 3 (305 receiving blinded therapy and 52 receiving calcium supplementation) and 277 in Year 4. During Years 1 through 3, patients received double-blind treatment with phosphate (1.0 g) or placebo twice daily for 3 days, etidronate (400 mg) or placebo daily for 14 days, and calcium (500 mg) daily for the remainder of each 91-day treatment cycle. During Year 4, open-label intermittent cyclic etidronate therapy (without preceding phosphate) was administered to all patients. Spinal bone density and vertebral fracture rates were the main outcome measures. RESULTS: During Year 3, etidronate therapy maintained the significant increases in spinal bone mineral density of the first 2 years. Over the 3-year period, proximal femur bone density increased in etidronate-treated patients. Etidronate therapy for 3 years significantly decreased the vertebral fracture rate in patients at higher risk for fracture (low spinal bone density and three or more vertebral fractures at study entry), as compared with nonetidronate treatment (228 versus 412 fractures per 1,000 patient-years, respectively; p < 0.05). After 1 year of open-label treatment, patients previously treated with etidronate maintained bone mass, and vertebral fracture rates in all groups were lower than in any other study period. There were no apparent serious adverse effects. CONCLUSIONS: Three years of intermittent cyclic etidronate therapy produced significant increases in spinal and hip bone density, with a significant reduction in vertebral fracture rates in patients at higher fracture risk. Maintenance of bone mass and low fracture rate were observed when etidronate was continued for an additional year.

Cyclical etidronate in the treatment of postmenopausal osteoporosis: efficacy and safety after seven years of treatment.

PURPOSE: To determine the efficacy and safety of cyclical etidronate for up to 7 years in the treatment of postmenopausal osteoporosis and to examine the effects of discontinuing treatment after 2 or 5 years of therapy. PATIENTS AND METHODS: Patients were randomized at entry into the original study in 1986 to blinded treatment for 2 years with either a calcium (placebo) or an intermittent cyclical etidronate regimen, which most patients continued for a third year. Following this phase of the study, patients were enrolled into an open-label, follow-up study (years 4 and 5), during which all patients received cyclical etidronate treatment. In the present double-blind study (years 6 and 7), patients were rerandomized to receive intermittent cyclical therapy with either etidronate or placebo; all patients received calcium. The treatment regimen consisted of 400 mg/day etidronate or placebo for 14 days, followed by 76 days of elemental calcium (500 mg/day); this cycle was repeated approximately 4 times in each year. Of the 193 patients who continued in years 6 and 7 of the study, 93 were randomized to receive cyclical etidronate and 100 were randomized to receive calcium only. For purposes of efficacy analyses, patients were categorized by their total years of cumulative etidronate treatment (7, 5, 4, or 2 years). There were 51, 46, 42, and 54 patients in the 7-, 5-, 4-, and 2-year groups, respectively. Annual assessments included lumbar spine bone mineral density (BMD), as measured by densitometry, and vertebral radiographs. RESULTS: The groups receiving cyclical etidronate during this 2-year study period (7- and 4-year groups) had statistically significant mean percent increases in spinal BMD of 1.8% and 2.2%, respectively (P < 0.05) at the week 104 observation time. The 5- and 2-year groups, which did not receive etidronate during this period, had mean values of 1.4% and 0.2%, respectively (not significant) at week 104. In the 7-, 5-, 4-, and 2-year groups, the increases in spinal BMD at the end of 7 years were 7.6%, 8.6%, 8.1%, and 3.9%, respectively; these values were statistically significant for all groups compared with original baseline (year 0) (P < 0.05). BMD of the femur and wrist was maintained throughout the 7-year period. The incidence and rate of vertebral fractures were lowest in patients with the longest exposure to etidronate. Etidronate was well tolerated during the study, with low incidences of gastrointestinal side effects and nonvertebral fractures. CONCLUSIONS: Long-term cyclical etidronate is a safe, effective, and well-tolerated treatment for postmenopausal osteoporosis. Bone mass is maintained for at least 2 years after treatment with etidronate is stopped; however, further gains in spinal bone mass are seen in patients who continue therapy.

Comparison of FDG-PET and sestamibi-SPECT in primary hyperparathyroidism.

UNLABELLED: Preoperative localization of hyperfunctioning parathyroid tissue in patients with primary hyperparathyroidism has been a longstanding diagnostic challenge. This study directly compared FDG-PET and sestamibi-SPECT for preoperative detection of abnormal parathyroid tissue. METHODS: Twenty-one consecutive patients with primary hyperparathyroidism were studied prospectively before surgical neck exploration. SPECT of the neck and chest was performed at 15 min and 2 hr after intravenous 99mTc-sestamibi. Regional body PET was performed 45 min after intravenous FDG. RESULTS: Surgery revealed 19 solitary parathyroid adenomas, 2 parathyroid adenomas in one patient; and 3 hyperplastic parathyroid glands in one patient, and 51 normal parathyroid glands. The diagnostic sensitivities for detection of parathyroid adenomas of 43% (9 of 21) for dual-phase sestamibi-SPECT and 86% (18 of 21) for FDG-PET were significantly different (p < 0.001). The difference in diagnostic specificities of 78% (40 of 51) for FDG-PET and 90% (46 of 51) for dual-phase sestamibi-SPECT approached statistical significance (p = 0.063). CONCLUSION: This study demonstrates that FDG-PET is more sensitive than sestamibi-SPECT in the preoperative localization of parathyroid adenomas in patients with primary hyperparathyroidism.

Rechallenge of patients who had discontinued alendronate therapy because of upper gastrointestinal symptoms.

BACKGROUND: There have been reports from physicians in clinical practice that up to 30% of patients taking bisphosphonate therapy develop upper gastrointestinal (UGI) symptoms, many or most of which they assume to be related to the drug. However, in several large placebo-controlled clinical trials of bisphosphonates, the incidence of UGI symptoms has been > or =30%, even among patients receiving placebo, perhaps reflecting a high background incidence of UGI events in osteoporotic patients. OBJECTIVE: To assess the relationship between alendronate treatment and UGI complaints in patients who had discontinued treatment with alendronate in clinical practice because of UGI symptoms, we compared the incidence of such events on rechallenge with alendronate or placebo. METHODS: This was a multicenter, double-blind trial in which postmenopausal women with osteoporosis who had previously discontinued alendronate therapy because of a UGI adverse experience were randomized to daily treatment with either alendronate 10 mg or matching placebo (1:1 ratio) for 8 weeks. The primary end point was the cumulative incidence of discontinuations due to any UGI adverse experience. Secondary end points were the incidence of any clinical adverse experiences and the percentage change from baseline in urinary N-telopeptide adjusted for urinary creatinine at week 8. RESULTS: A total of 172 women were included in the study. They were a mean of 20.9 years past menopause, ranging in age from 41 to 90 years (mean, 67.0 years); 90.7% were white. On rechallenge, 14.8% (13/88) of patients in the alendronate group and 16.7% (14/84) in the placebo group discontinued treatment because of UGI adverse experiences. CONCLUSION: The results of this study suggest that many UGI adverse experiences reported during therapy with alendronate may reflect a high background incidence of UGI complaints and an increased sensitivity to detection of such complaints, rather than a causal relationship to therapy.

Stress fractures in young athletic women: case reports of unsuspected cortisol-induced osteoporosis.

Stress fractures in the female athlete are common events, usually occurring in the lower limb and less often in the pelvic girdle. Two cases are presented of young women athletes who presented with initial lower limb stress fractures, but subsequently fractures of the pelvis and hip thought to be associated with their athletic activity. After careful medical evaluation, they were diagnosed with Cushing's syndrome. One patient had a microadenoma of the pituitary gland secreting excessive amounts of ACTH, and the other had a benign adenoma of the left adrenal gland. Both women had significant decreases in their spinal mineral density. After treatment, partial reversal of these spinal losses occurred. Although stress fractures in the female athlete might be common and thought to be associated with problems of amenorrhea, presentation of unusual anatomical sites for these fractures necessitates a more thorough evaluation for correctable secondary causes.

Bisphosphonate therapy.

The bisphosphonates are long-lived synthetic analogs of pyrophosphate, a natural, short-lived inhibitor of bone. Oral doses share similar qualities (ie, they inhibit bone resorption, poor absorption, and potential gastrointestinal irritants), but each one has a unique spectrum of potency and a probable mechanism of action. The parent compound, etidronate, was first used in multicentered trials for the treatment of primary osteoporosis and showed some success in increasing bone density and perhaps controlling fracture rates. The recently approved drug alendronate is a more potent agent than etidronate, produces a greater increase in bone density, and decreases fractures. Oral and intravenous pamidronate have similar positive effects on bone density. Studies with tiludronate, risedronate, and clodronate show similar promise as therapeutic agents.

Angiotropic large-cell lymphoma in a patient with adrenal insufficiency.

Angiotropic large-cell lymphoma is a rare disorder characterized by a proliferation of malignant lymphoid cells within the lumina of small vessels. The skin and central nervous system are typically affected; however, involvement of other organs has been described. We document an unusual case of this disorder in a patient who suffered clinically significant adrenal insufficiency and subsequently died. Autopsy disclosed angiotropic large-cell lymphoma involving both adrenal glands.

Hyperparathyroidism, hyperthyroidism, and Cushing's disease.

In this article, normal and hyperactive states of parathyroid, thyroid, and cortisol production are examined. Their role in bone loss and the rationale for therapeutic intervention are also discussed.

Prevention and osteoporosis management.

BACKGROUND: Primary osteoporosis affects one in four women over the age of 65 and reflects lifelong processes and trends. SUMMARY: Skeletal bone constantly repairs the microscopic damage it sustains as a result of the normal activities of living. Women achieve their maximum bone density by the close of adolescence. Hereditary, nutritional, hormonal, and life-style factors affect the process of osteoporosis. Bone densitometry can detect very small deficits long before losses become clinically apparent. Intervention can halt osteoporosis at any point and perhaps increase bone density, but no known therapy can restore the normal bone architecture once it is lost. KEY POINTS: Women should maintain an adequate intake of calcium throughout their lifetime, especially during adolescence. Bone densitometry at the time of menopause detects preclinical osteoporosis and enables physicians to start therapy to preserve the bone structure.

From bathtub ring to osteoporosis: a clinical review of the bisphosphonates.

BACKGROUND: Etidronate and pamidronate are bisphosphonates, a class of chemical compounds originally used to soften hard water and prevent soap scum. Etidronate was serendipitously found to abate calcification in a child with myositis ossificans progressiva. OBJECTIVE: Review the basic pharmacology of these compounds, as well as clinical uses of the approved and nonapproved forms. DISCUSSION: Etidronate is approved for the treatment of hypercalcemia, Paget's disease of bone, and ectopic calcification, and has been used to treat hyperparathyroidism and nephrolithiasis with limited success. Recently it has been used to treat osteoporosis. Pamidronate is approved to treat hypercalcemia. These two drugs are the only bisphosphonates available in the United States. CONCLUSIONS: Clinical trials with etidronate have aroused widespread interest in the application of bisphosphonates to treat osteoporosis. Many trials are underway to evaluate these new drugs. More information will be available within the next 5 years.

Chemical and histological features of men with osteoporosis.

Six men (average age, 42) underwent evaluation for idiopathic osteoporosis. Standard measurements of serum and urine were studied. Lumbar skeletal mineral density was measured by dual-photon absorptiometry. Skeletal biopsies of the iliac crest were obtained after double-labeling with tetracycline. Average renal cyclic adenosine monophosphate and urinary calcium values were elevated. Lumbar spinal density was 72% of age-matched norms, and histomorphometric analyses of bone revealed decreased trabecular bone volume and formation rate and increased trabecular osteoid area, osteoclast number, and calcification rate. The results suggest that idiopathic osteoporosis in these men is associated with increased parathyroid hormone secretion as assessed by increased renal cyclic adenosine monophosphate and high skeletal remodeling activity.

Role of alendronate and risedronate in preventing and treating osteoporosis.

Alendronate and risedronate, the two oral bisphosphonates approved in the United States for preventing and treating osteoporosis, have never been compared in direct head-to-head trials, but they appear to have similar pharmacokinetics, drug interactions, adverse effect profiles, and efficacy. Alendronate, however, can be given as a once-weekly dose, whereas risedronate is not yet available in this dosage form. On the other hand, alendronate is not approved for preventing glucocorticoid-induced osteoporosis, whereas risedronate carries this indication.

Raloxifene: a new choice for treating and preventing osteoporosis.

Selective estrogen receptor modulators (SERMs) are a new class of drugs that provide a new option for addressing the health challenges of postmenopausal women. This review discusses the proposed mechanism of action of SERMs and describes clinical findings on raloxifene, a SERM now available for treating and preventing osteoporosis.