Incidence of nonvertebral fractures in relation to time on treatment and bone density in glucocorticoid-treated patients: a retrospective approach.

The effects of duration of treatment and bone mineral density (BMD) on nonvertebral fracture in 560 glucocorticoid users were examined by using baseline and retrospective data from 2 parallel studies assessing the efficacy and safety of alendronate therapy. Baseline spine and hip BMD were significantly (P < 0.01) lower with increased time spent receiving glucocorticoids. Forty-three patients (7.7%) had experienced at least 1 nonvertebral fracture after starting glucocorticoid treatment. The hazard function for nonvertebral fracture occurrence increased significantly (P < 0.01) with time spent receiving glucocorticoids: fracture incidence per 1,000 person-years on glucocorticoids was 18 (< 5 years), 31 (5-10 years), and 35 (> 10 years). Patients with a history of nonvertebral fractures after starting glucocorticoid treatment had significantly lower lumbar spine (P < 0.01) and hip (< 0.01) BMD value than those without fractures. This retrospective analysis suggests that a BMD measurement of spine and hip may identify risk for nonvertebral fractures in a heterogeneous population of glucocorticoid users.

Treatment of male osteoporosis: recent advances with alendronate.

Overall, the data from the two alendronate studies clearly document the efficacy and safety of alendronate in osteoporotic men. The positive effects of alendronate on BMD, markers and fractures are very consistent between studies. Importantly, they are also very consistent with the results of multiple clinical studies conducted in postmenopausal women with osteoporosis. Treatment with 10 mg alendronate for 2 years produced significant and clinically meaningful increases in BMD, similar to those previously observed in postmenopausal women. Data from studies including men and women confirm the similarity of response suggested by single-gender studies. Consistent with much larger studies in postmenopausal women, alendronate 10 mg/day also reduced the incidence of new vertebral fracture and, correspondingly, reduced height loss. The safety and tolerability of alendronate in men was favorable and consistent with the safety profile previously observed in postmenopausal women. Alendronate represents an important and needed therapeutic advancement in the management of osteoporosis in men.

Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial.

OBJECTIVE: To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS: This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS: The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION: Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

Alendronate in early postmenopausal women: effects on bone mass during long-term treatment and after withdrawal. Alendronate Osteoporosis Prevention Study Group.

We studied the effect on bone mass of alendronate treatment for 5 yr and its withdrawal. Four hundred and forty-seven postmenopausal women with normal bone mass entered a 3-yr randomized trial followed by a 2-yr open label extension. Three hundred and eleven women completed the first 3 yr, and 263 consented to continue and completed the extension. We are reporting data from groups using the dose of alendronate currently approved for osteoporosis prevention (5 mg) or from the group in which alendronate treatment was withdrawn: 52 women received alendronate (5 mg) for 5 yr (group I), 56 received 3 yr of placebo followed by alendronate (5 mg) for 2 yr (group II), and 52 received alendronate (20 mg) for 2 yr followed by 3 yr off therapy (group III). In group I, alendronate (5 mg) increased bone mineral density (BMD) at the spine and trochanter by 2.5-3.2% (P < 0.001 vs. baseline) and stabilized total body and femoral neck BMD (change vs. baseline, P = NS) over 5 yr. By the end of 5 yr, BMD was comparable at the spine, hip, and total body in groups I and III. The 3-yr decrease in BMD after withdrawal of alendronate (20 mg) in group III was 1.8-5.7% (P < 0.01 vs. baseline) and similar to the 3-yr decrease in BMD in group II during the initial 3 yr. In conclusion, alendronate (5 mg) for 5 yr or alendronate (20 mg) for 2 yr followed by 3 yr off therapy prevented postmenopausal bone loss. After withdrawal of alendronate (20 mg), bone loss resumed at the normal early postmenopausal rate.

Effects of alendronate on bone quality and remodeling in glucocorticoid-induced osteoporosis: a histomorphometric analysis of transiliac biopsies.

Effects of alendronate (ALN) on bone quality and turnover were assessed in 88 patients (52 women and 36 men aged 22-75 years) who received long-term oral glucocorticoid exposure. Patients were randomized to receive oral placebo or alendronate 2.5, 5, or 10 mg/day for 1 year and stratified according to the duration of their prior glucocorticoid treatment. Transiliac bone biopsies were obtained for qualitative and quantitative analysis after tetracycline double-labeling at the end of 1 year of treatment. As previously reported in glucocorticoid-induced osteoporosis, low cancellous bone volume and wall thickness were noted in the placebo group as compared with normal values. Alendronate treatment was not associated with any qualitative abnormalities. Quantitative comparisons among the four treatment groups were performed after adjustment for age, gender, and steroid exposure. Alendronate did not impair mineralization at any dose as assessed by mineralization rate. Osteoid thickness (O.Th) and volume (OV/BV) were significantly lower in alendronate-treated patients, irrespective of the dose (P = 0.0003 and 0.01, respectively, for O.Th and OV/BV); however, mineral apposition rate was not altered. As anticipated, significant decreases of mineralizing surfaces (76% pooled alendronate group; P = 0.006), activation frequency (-72%; P = 0.004), and bone formation rate (-71%; P = 0.005) were also noted with alendronate treatment. No significant difference was noted between the changes observed with each dose. Absence of tetracycline label in trabecular bone was noted in approximately 4% of biopsies in placebo and alendronate-treated groups. Trabecular bone volume, parameters of microarchitecture, and resorption did not differ significantly between groups. In conclusion, alendronate treatment in patients on glucocorticoids decreased the rate of bone turnover, but did not completely suppress bone remodeling and maintained normal mineralization at all alendronate doses studied. Alendronate treatment did not influence the osteoblastic activity, which is already low in glucocorticoid-induced osteoporosis.

Weekly administration of alendronate: rationale and plan for clinical assessment.

OBJECTIVE: This paper describes the rationale and supporting data for once-weekly dosing of alendronate. BACKGROUND: Alendronate sodium, a bisphosphonate that potently inhibits bone resorption, has been shown to increase bone mass and substantially reduce the incidence of osteoporotic fractures, including fractures of the hip. The standard regimen of daily administration has generally been well tolerated. However, weekly administration may provide greater convenience to patients without compromising efficacy or tolerability. The pharmacokinetics of alendronate and bone remodeling theory predict similar efficacy for weekly and daily administration if the cumulative dose is the same. Bone resorption in individual remodeling units normally proceeds for approximately 2 weeks; alendronate inhibits the rate and extent of resorption. Because the half-life of residence on bone surfaces is several weeks, weekly administration of alendronate should inhibit bone resorption to an overall extent similar to that of daily dosing, thereby producing similar effects on bone mass and strength. Animal studies demonstrate that both weekly and daily parenteral administration of alendronate effectively increase bone mass and strength, but confirmation of efficacy is needed for weekly oral dosing in humans. Although daily bisphosphonates (alendronate and risedronate) elicited esophageal irritation in a canine model of gastroesophageal reflux, weekly dosing with alendronate at a higher unit dose did not. Thus, the lower frequency of weekly dosing with a higher unit dose may actually reduce the risk of upper gastrointestinal irritation compared with daily administration of a lower dose. CONCLUSIONS: Current safety and efficacy data justify further investigation of once-weekly dosing of alendronate. Two positive-control, double-blind, randomized trials of osteoporosis treatment and prevention are currently being performed to assess the comparability of weekly, biweekly, and daily dosing of alendronate with regard to effects on bone density, safety, and tolerability.

The clinical tolerability profile of alendronate.

Alendronate is a potent bisphosphonate that is effective in preventing osteoporotic fractures. Clinical trial data involving over 17,000 women provide a large, placebo-controlled experience from which alendronate has been demonstrated to be safe and well tolerated. We review the safety profile of alendronate in the context of its pharmacology, preclinical information and published literature on bisphosphonates. The clinical data include information from 1) the two primary Phase III osteoporosis treatment studies involving 994 women with postmenopausal osteoporosis treated with alendronate for up to 3 years; 2) upper gastrointestinal (GI) tolerability data (including special subgroup analyses) from the Fracture Intervention Trial (FIT), involving 2027 women with prior vertebral fractures; 3) an endoscopy study, and 4) postmarketing experience. Because all bisphosphonates have the potential to irritate the upper GI mucosa, we specifically investigated the safety and tolerability profile with respect to the upper GI tract. In the Phase III trials, alendronate 5 or 10 mg/day was well tolerated, with no increase relative to placebo in the incidence of overall adverse experiences (ie, inclusive of all events, not just those related to the GI tract). In the Phase III trials, alendronate 5 mg/day or 10 mg/day was well tolerated, with no increase relative to placebo in the incidence of overall adverse experiences. The incidence of upper gastrointestinal adverse experiences, overall, was similar among alendronate 5 mg or 10 mg and placebo, with abdominal pain and dysphagia being the only individual adverse experiences that were significantly increased (with alendronate 10 mg). Esophageal adverse experiences were uncommon, being reported in 8 (2.0%) patients receiving placebo and 9 (4.6%) patients taking alendronate 10 mg. None of the events occuring on alendronate therapy were serious or resulted in discontinuation. Tolerability was not affected by a wide range of concomitant medications including nonsteroidal anti-inflammatory drugs. Additional analyses of the 2027 postmenopausal women with vertebral fractures enrolled in FIT demonstrated that alendronate use was not associated with a significant increase in upper GI events, esophageal events, or gastroduodenal adverse events, even among women at high risk for upper GI complications (those older than 75 yr, those with previous upper GI disease, or those using NSAIDs). Esophageal adverse experiences (including esophagitis and esophageal ulcers) have been reported with alendronate in postmarketed use. A high proportion of these reports involved patients who did not follow the dosing instructions and probably relate to the irritant potential of refluxed gastric acid containing alendronate. Consistent with the antiresorptive mechanism of action of alendronate, asymptomatic decreases in serum calcium and phosphate were observed with alendronate treatment in the clinical trials. There were no other laboratory changes noted with alendronate. Now marketed in 78 countries and used by over 3 million women, the safety profile of alendronate, when dosed appropriately, has been consistent with that of the clinical trial experience. In view of the increased morbidity and mortality associated with fractures, and the proven efficacy of alendronate to reduce fracture risk, the benefit/risk ratio of alendronate remains highly favourable.

Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group.

BACKGROUND: Osteoporosis is a common complication of long-term glucocorticoid therapy for which there is no well-proved preventive or restorative treatment. METHODS: We carried out two 48-week, randomized, placebo-controlled studies of two doses of alendronate in 477 men and women, 17 to 83 years of age, who were receiving glucocorticoid therapy. The primary end point was the difference in the mean percent change in lumbar-spine bone density from base line to week 48 between the groups. Secondary outcomes included changes in bone density of the hip, biochemical markers of bone turnover, and the incidence of new vertebral fractures. RESULTS: The mean (+/-SE) bone density of the lumbar spine increased by 2.1+/-0.3 percent and 2.9+/-0.3 percent, respectively, in the groups that received 5 and 10 mg of alendronate per day (P<0.001) and decreased by 0.4+/-0.3 percent in the placebo group. The femoral-neck bone density increased by 1.2+/-0.4 percent and 1.0+/-0.4 percent in the respective alendronate groups (P<0.01) and decreased by 1.2+/-0.4 percent in the placebo group (P<0.01). The bone density of the trochanter and total body also increased significantly in the patients treated with alendronate. There were proportionally fewer new vertebral fractures in the alendronate groups (overall incidence, 2.3 percent) than in the placebo group (3.7 percent) (relative risk, 0.6; 95 percent confidence interval, 0.1 to 4.4). Markers of bone turnover decreased significantly in the alendronate groups (P<0.001). There were no differences in serious adverse effects among the three groups, but there was a small increase in nonserious upper gastrointestinal effects in the group receiving 10 mg of alendronate. CONCLUSIONS: Alendronate increases bone density in patients receiving glucocorticoid therapy.

Alendronate prevents postmenopausal bone loss in women without osteoporosis. A double-blind, randomized, controlled trial. Alendronate Osteoporosis Prevention Study Group.

BACKGROUND: Preventing bone loss associated with menopause and aging and maintaining the normal micro-architecture of bone provide important opportunities for the prevention of osteoporosis and fractures. OBJECTIVE: To determine the safety and efficacy of alendronate, an aminobisphosphonate, for preventing postmenopausal bone loss. DESIGN: 3-year double-blind, randomized, placebo-controlled trial. SETTING: 15 osteoporosis centers throughout the world. PARTICIPANTS: 447 women who had recently experienced menopause (6 to 36 months before study entry). INTERVENTION: Participants were randomly assigned to one of five regimens: oral placebo; oral alendronate, 1, 5, or 10 mg/d; or oral alendronate, 20 mg/d for 2 years followed by placebo during the third year (20/0 mg/d). MEASUREMENTS: Bone mineral density was measured by dual-energy x-ray absorptiometry. Bone turnover and bone quality were assessed with biochemical markers and bone histomorphometry. RESULTS: Alendronate at 5, 10, and 20/0 mg/d increased bone mineral density from baseline at the lumbar spine, femoral neck, and trochanter by 1% to 4% and in the total body by 0.3% to 1.0%; placebo led to losses of 2% to 4% at these sites. Alendronate, 1 mg/d, attenuated losses relative to those seen with placebo. Alendronate decreased markers of bone resorption to a new steady state by 3 months and decreased markers of bone formation by 6 to 12 months. Bone quality remained normal. At all dosages studied, alendronate had a safety and tolerability profile similar to that of placebo. CONCLUSIONS: In early postmenopausal women, alendronate given for 3 years at dosages of 5 mg/d or greater prevented the loss of bone mineral density at the spine and hip and in the total body. Alendronate seems to be a safe and effective nonhormonal option for prevention of postmenopausal bone loss.

Esophagitis associated with the use of alendronate.

BACKGROUND: Alendronate, an aminobisphosphonate and a selective inhibitor of osteoclast-mediated bone resorption, is used to treat osteoporosis in postmenopausal women and Paget's disease of bone. Aminobiphosphonates can irritate the upper gastrointestinal mucosa. METHODS: We describe three patients who had severe esophagitis shortly after starting to take alendronate and also analyze adverse esophageal effects reported to Merck, the manufacturer, through postmarketing surveillance. RESULTS: As of March 5, 1996, alendronate had been prescribed for an estimated 475,000 patients worldwide, and 1213 reports of adverse effects had been received. A total of 199 patients had adverse effects related to the esophagus; in 51 of these patients (26 percent), including the 3 we describe in case reports, adverse effects were categorized as serious or severe. Thirty-two patients (16 percent) were hospitalized, and two were temporarily disabled. Endoscopic findings generally indicated chemical esophagitis, with erosions or ulcerations and exudative inflammation accompanied by thickening of the esophageal wall. Bleeding was rare, and stomach or duodenal involvement unusual. In patients for whom adequate information was available, esophagitis seemed to be associated with swallowing alendronate with little or no water, lying down during or after ingestion of the tablet, lying down during or after ingestion of the tablet, continuing to take alendronate after the onset of symptoms, and having preexisting esophageal disorders. CONCLUSIONS: Alendronate can cause chemical esophagitis, including severe ulcerations, in some patients. Recommendations to reduce the risk of esophagitis include swallowing alendronate with 180 to 240 ml (6 to 8 oz) of water on arising in the morning, remaining upright for at least 30 minutes after swallowing the tablet and until the first food of the day has been ingested, and discontinuing the drug promptly if esophageal symptoms develop.

Overexpression of parathyroid hormone-related protein or parathyroid hormone in transgenic mice impairs branching morphogenesis during mammary gland development.

Parathyroid hormone-related protein (PTHrP) was originally discovered as the tumor product that causes humoral hypercalcemia of malignancy. PTHrP is now known to be widely expressed in many normal fetal tissues where it may participate in the regulation of organogenesis. In this report, we document that overexpression of PTHrP in myoepithelial cells in the mammary glands of transgenic mice resulted in a form of breast hypoplasia characterized by a profound defect in branching morphogenesis of the developing mammary duct system. In addition, transgenic mice manifested a defect in lobuloalveolar development during pregnancy that seemed to be, in part, the consequence of an impaired ability to form terminal ducts in response to estrogen and progesterone stimulation. The effects of PTHrP on branching morphogenesis during breast development appeared to be the result of amino-terminal PTH-like sequences that signal through the PTH/PTHrP receptor, since overexpression of parathyroid hormone itself in the mammary glands of transgenic mice caused a similar development phenotype, and delivery of PTHrP (1-36) via locally implanted slow-release pellets impaired breast development in normal mice. These results suggest that PTHrP, which is a native product of mammary epithelial and myoepithelial cells may participate in normal breast development, perhaps as a locally secreted growth inhibitor.

Relative overexpression of the parathyroid hormone-related protein gene in human leiomyomas.

Uterine leiomyomas or fibroids are common among women of reproductive age, but their biology is poorly understood. The PTH-related protein (PTHrP) has been identified in a number of sites throughout the reproductive tract. We, therefore, examined whether fibroids express PTHrP mRNA and compared their level of expression with that in normal myometrium. Total RNA prepared from fibroid tissue and corresponding normal myometrium from seven patients was examined by RNase protection analysis. In all cases, fibroid and myometrial tissue expressed PTHrP, and in six of seven cases, PTHrP expression was higher in fibroids than in normal myometrium. Cultured fibroid cells from four patients also expressed higher levels of PTHrP mRNA than corresponding cultured normal myometrial cells. Tissue extracts from eight patients and conditioned medium from cultured cells from nine patients were examined for PTHrP immunoreactivity using a two-site immunoradiometric assay. In tissue extracts and conditioned medium, the mean PTHrP concentration was significantly higher in fibroids than normal myometrium. Immunohistochemical staining of fibroid and myometrial tissue was positive for PTHrP. Finally, PTHrP-(1-34) induced a dose-dependent increase in cAMP in fibroid and myometrial cells in vitro. These findings suggest that PTHrP may have an autocrine/paracrine function in regulating myometrial physiology and may play a role in regulating fibroid growth or differentiation.

Stretch-induced parathyroid hormone-related peptide gene expression in the rat uterus.

We previously observed a peak in parathyroid hormone-related peptide (PTHrP) mRNA expression in preterm rat myometrium and found that this peak was dependent on intrauterine occupancy. We explored the possibility that mechanotransduction might control PTHrP gene expression in the uterus. This was done by developing an intrauterine balloon system that allowed us to reproduce experimentally the mechanical effects of the fetal pup in utero. An increase in PTHrP mRNA in the unoccupied horn of a unilaterally pregnant rat could be elicited as rapidly as 1 h after balloon inflation and was maintained for up to 72 h. The same response was seen in uterine horns from virgin animals and could be reproduced by three different methods of imposing a physical stretch. Balloon-induced stretch also increased mRNA expression in a muscle bath system in vitro. Mechanotransduction appears to be largely, if not entirely, responsible for the preterm peak in PTHrP mRNA expression.

Intrauterine occupancy controls expression of the parathyroid hormone-related peptide gene in preterm rat myometrium.

The parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHRP) genes are members of a gene family. Whereas PTH is a classical peptide hormone, mounting evidence suggests that the PTHRP may have predominately local actions. We report here that the PTHRP gene is expressed in rat myometrium, with a major peak in PTHRP mRNA expression occurring in the 48 hr immediately preceding parturition. A similar peak in peptide content was found in tissue extracts by biological and immunological assays, but the PTHRP could not be detected in the peripheral circulation or in uterine vein plasma during late gestation. By in situ hybridization histochemistry, PTHRP mRNA was demonstrated in both the longitudinal and circular layers of smooth muscle but was absent in the endometrium. The rise in myometrial PTHRP mRNA in late gestation was dependent upon intrauterine occupancy; it was greatly reduced or absent in nongravid uterine horns. These findings indicate that the expression of the PTHRP gene in preterm myometrium is under the control of a local stimulus and suggest that the PTHRP may play a paracrine or autocrine role in the uterus during the antepartum period, possibly involving myometrial contractility.