A. John Yates

Alendronate Prevents Postmenopausal Bone Loss in Women without Osteoporosis: A Double-Blind, Randomized, Controlled Trial

Osteoporosis is characterized by low bone mass and architectural changes in bone that render the skeleton brittle and susceptible to fracture [1]. As the elderly population grows, the worldwide annual incidence of hip fractures is projected to increase from 1.7 million in 1990 to 6.3 million by 2050, placing great economic strain on health care systems [2]. Currently, a 50-year-old woman is estimated to have a risk as high as 40% for sustaining a fracture related to osteoporosis at some point in the future [3]. The age-adjusted risk for fracture seems to be increasing, and this risk may be an underestimate for the future [4]. Bone loss after menopause, which results in low bone density, is an important determinant of risk for fracture, although other factors (such as advanced age, hip geometry, and falls and injuries) also contribute [5, 6]. Bone loss is most rapid during the first few years after menopause, but evidence suggests that the rate of loss also becomes accelerated in advanced old age [7, 8]. One strategy to reduce the number of fractures in postmenopausal women is to begin treatment for osteoporosis only in patients who are at high risk for fracture, including those with osteoporosis or previous fragility fractures. Pharmacologic therapy in women with osteoporosis with or without fractures reduces the incidence of fracture by about 50% [9, 10]. However, half of women who would have sustained fractures without treatment still do so with treatment. Thus, preventing rather than treating osteoporosis is a more appealing clinical objective because it can avoid the increased risk for fracture. There may also be an advantage in terms of preserving the normal microarchitecture of bone. Preventing bone loss associated with menopause and aging and maintaining normal microarchitecture provide important opportunities for the prevention of osteoporosis and fractures. Estrogen is effective in preventing bone loss in early and late postmenopausal women, but it must be taken over the long term to decrease the incidence of vertebral and hip fractures [11]. Estrogen also relieves menopausal symptoms and, in epidemiologic cohort studies, seemed to protect against cardiovascular disease. However, most women who begin estrogen therapy do not continue it for more than a year, in part because of such side effects as breast tenderness, headache, fluid retention, and withdrawal bleeding [12, 13]. Although the benefits of estrogen therapy outweigh the risks in most women, concern about risk for breast cancer is sufficiently great that many women avoid estrogen therapy [14, 15]. Alendronate sodium (monosodium 4-amino, 1-hydroxybutylidene-1, 1-bisphosphonate) is a potent and selective inhibitor of osteoclast-mediated bone resorption. Studies in animals with low bone mineral density have shown that alendronate therapy is associated with increased bone mass of normal quality and increased bone strength [16]. Alendronate treatment of osteoporosis in postmenopausal women induces progressive increases in bone density and a reduction in the incidence of new fractures of the vertebrae, hip, and forearm in osteoporotic women [9, 10]. We performed a 3-year randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy of alendronate therapy in preventing bone loss in healthy women who had recently experienced menopause. Methods Study Participants Healthy women aged 40 to 59 years who had experienced menopause 6 to 36 months before enrollment were eligible to participate in this study. Women were excluded if their spine bone mineral density was more than 2 SDs above or below normal peak bone mineral density or if they had a history of nontraumatic spine or hip fracture. Women with disorders of bone and mineral metabolism were also excluded, as were those with recent (within 1 year of study entry) major upper gastrointestinal diseases (such as peptic ulcer, esophageal disease, and malabsorption). Other exclusion criteria were previous treatment with bisphosphonates or fluoride (>1 mg/d) or treatment within the 12 months before enrollment with estrogen, progestin, calcitonin, glucocorticoids, anticonvulsant agents, phosphate-binding antacids, or excessive vitamin A or vitamin D. Women who regularly used (>four times per week) any medication that had the potential to cause gastrointestinal irritation (such as aspirin), who smoked more than 20 cigarettes per day, or who drank three or more alcoholic beverages per day were also excluded. Four hundred forty-seven women met the inclusion criteria and were enrolled at 15 centers throughout the world. The target sample size of 250 women completing the study was selected to detect a difference in bone density of 2.4% between an individual alendronate dosage and placebo at a P value of 0.05 or less, with 95% power using an SD of 3.3% that was obtained from 1-year bone density data in placebo recipients [17]. All centers conducted the study with appropriate approval from the institutional review boards, and all participants gave informed consent. Treatment Participants were randomly assigned (in allocation blocks of five) to one of five regimens: placebo for 3 years; alendronate at 1, 5, or 10 mg/d for 3 years; or alendronate at 20 mg/d for 2 years followed by placebo for 1 year (20/0 mg/d). In all groups, double-blinding was maintained for all 3 years. Alendronate and placebo tablets were identical in size, shape, and color. The women were instructed to take the study drug daily at least 1 hour before breakfast or, as a less desirable alternative, at least 2 hours after a meal and 1 hour before the next meal. All participants also received a daily supplement of calcium carbonate (Os-Cal 500, Smith-Kline Beecham Consumer Brands, LP, Pittsburgh, Pennsylvania, or the equivalent) unless dietary calcium intake exceeded 1000 mg/d. This supplement was usually taken with the evening meal. After beginning therapy, each participant was seen at months 1 and 3 and every 3 months thereafter. Eight participants (four in the placebo group and four in the 1-mg/d group) lost more than 6% of their spine bone density at 24 months relative to their baseline measurements and were therefore designated fast bone losers. Seven of these participants completed the study; from month 24 to the end of the study, they received 5 mg of open-label alendronate per day. The other patient discontinued therapy at month 24. Bone Mineral Density Bone mineral density of the spine, proximal femur, total body, and forearm was measured every 6 months by dual-energy x-ray absorptiometry with a Hologic QDR-1000, 1000/W, or 2000 densitometer (Waltham, Massachusetts) or a Lunar DPX-L densitometer (Madison, Wisconsin). One bone density quality assurance center (Oregon Osteoporosis Center) that remained blinded to treatment allocation was responsible for the quality control of all participant and phantom calibration scans [18]. Factors to correct for machine calibration drift were applied as necessary. The primary end point was bone mineral density of the lumbar spine; the other most important end points were bone mineral density of the femoral neck, trochanter, and total body. Bone mineral density of the total body, total hip, and forearm was measured at the centers that had densitometers capable of performing these measurements (11 centers measured bone mineral density of the total body; 10 centers measured bone mineral density of the total hip and forearm). Biochemical Markers and Indices of Mineral Metabolism Fasting serum and urine samples (second morning void) were obtained at all clinic visits except those in months 27 and 33. The resorption markers included urine deoxypyridinoline, measured by high-pressure liquid chromatography, and (in a subgroup of 268 participants) urine N-telopeptide cross-links of type I collagen (Ostex, Seattle, Washington). Each of these markers was expressed as a ratio to urine creatinine. Serum osteocalcin levels, measured by radioimmunoassay (INCSTAR, Stillwater, Nebraska), and serum bone-specific alkaline phosphatase levels were used to assess the rate of bone formation. Levels of serum calcium, phosphorus, intact parathyroid hormone (measured by immunoradiometric assay), and 1,25 dihydroxyvitamin D (measured by competitive binding assay) were also determined to assess the effects of treatment on mineral metabolism. N-telopeptide levels were measured by Medical Research Laboratories (Highland Heights, Kentucky). All other assays were done at Corning-Nichols Institute (San Juan Capistrano, California). Safety Evaluations At each visit, vital signs were measured and any new or worsening symptoms were recorded. Physical examinations were performed at the baseline, month 3, and yearly visits. Standard laboratory safety evaluations (including evaluations of hematologic, renal, and liver function) were performed at every visit. Investigators reported any unfavorable or unintended clinical or laboratory events as adverse experiences. After 3 years of therapy, biopsy specimens of transiliac bone were obtained for histologic and histomorphometric assessment from 55 women who provided specific informed consent for this procedure. These analyses were performed, as previously described, by a single investigator who was blinded to treatment groups [19]. Statistical Analysis The Tukey trend test [20] was used to assess the trend in response with increasing alendronate dosages. The 20/0-mg/d group was excluded from this test because of the change in dosage. This test uses the minimum P value, adjusted for multiplicity [21], that was obtained from tests of the regression sloped on three dosage scalings. The test is done in a stepwise manner, with the highest dosage eliminated, until the minimum P value exceeds 0.05. Dose-response relations were examined for the responses of the percentage change in bone density variables, natural logarithm (fraction of the baseline value) for biochemical variabl

Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate: A randomized, placebo-controlled trial

PURPOSE The potent bisphosphonates offer great promise in the management of Pagets disease of bone, but are currently available only as parenteral preparations in most countries. There is a need for a well-tolerated, oral therapy. Furthermore, none of the currently available therapies have been rigorously demonstrated to heal the lytic bone lesions characteristic of this condition. Alendronate is a potent new oral aminobisphosphonate that has shown promising effects on Pagets disease in preliminary studies. METHODS We report a double-blind, randomized comparison of oral alendronate 40 mg/day and placebo over 6 months in 55 patients with Pagets disease. Efficacy was determined from measurements of biochemical indices of bone turnover (serum alkaline phosphatase and urine N-telopeptide) and blinded radiologic assessment of lytic bone lesions. RESULTS N-telopeptide excretion declined by 86% and serum alkaline phosphatase by 73% in patients receiving alendronate, but remained stable in patients receiving placebo (P < 0.001 between groups for both indices). Responses were similar whether or not patients had previously received bisphosphonate treatment. Alendronate treatment normalized alkaline phosphatase in 48% of patients. Forty-eight percent of alendronate-treated patients showed radiologic improvement in osteolysis whereas in the placebo group only 4% improved (P = 0.02 for between-groups comparison). No patient in either group showed worsening of osteolysis. Bone histomorphometry indicated that alendronate tended to normalize turnover indices. There was no evidence of abnormal mineralization in bone biopsies taken from 12 alendronate-treated subjects. The treatment was well tolerated. CONCLUSION Oral alendronate appears to be a safe and effective therapy for Pagets disease and results in healing of lytic bone lesions.

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.

Radiographic absorptiometry in the diagnosis of osteoporosis

Radiographic absorptiometry (RA) is a technique for bone mass measurement from radiographs of peripheral sites, most commonly the hand or heel. The principle was first described in 1939, and RA became relatively widely used as a research technique in the 1960s, although interest in RA subsequently dwindled as precise nonradiographic densitometry techniques became available. Recently, however, computerized image processing has been applied to radiography, with the result that current RA techniques applicable to a routine clinical setting are as precise and accurate as dual-energy or single-energy x-ray absorptiometry (DXA or SXA). In addition, recent studies demonstrate that the strength of association between low bone mass measured by RA and fracture risk is comparable to that for other forms of bone mass measurement. The relatively low cost and lack of need for specialized equipment make RA a highly attractive option for the diagnosis of osteoporosis that is available to specialist and nonspecialist physicians alike.

Bisphosphonate Effects and the Bone Remodeling Transient

Published randomized clinical trial data for alendronate, given at a dose of 10 mg/day, were fitted by a computer algorithm to the currently accepted model of the bone remodeling process. The purpose was to determine how much of the reported improvement in lumbar spine bone density could be attributed to the inevitable remodeling transient and how much might represent positive bone balance. Very good fits to the clinical data were easily obtained, indicating the general validity of current syntheses of bone remodeling biology. The best fit was provided by simulations produced by combinations of 36–38% suppression of remodeling activation and positive remodeling balance ranging from 1.1 to 1.4% per year. Whole body bone biomarker changes would have suggested both a slightly greater degree of suppression and a higher baseline level of remodeling than could be provided by any of the simulations if they were to fit the clinical data. Either regional skeletal heterogeneity or lack of a one‐to‐one quantitative relationship between remodeling changes and biomarker changes may explain the discrepancies between the two approaches.

Evidence that increased calcium intake does not prevent Early postmenopausal bone loss

Calciums ability to prevent bone loss in early postmenopausal women is controversial. We used data on 394 women from the placebo group of the Early Postmenopausal Interventional Cohort study, a clinical trial of alendronate, to investigate the relation of calcium intake to bone loss. Calcium intake was recorded, and bone mineral density (BMD) (in the lumbar spine, total body, forearm, and hip) and biochemical markers of bone turnover (serum total alkaline phosphatase, serum osteocalcin, and urinary N-telopeptide crosslink levels) were measured at baseline and annually thereafter. Women whose baseline calcium intake was <500 mg/d were advised to increase their calcium intake. Mean (+/- SE) BMD decreased by 1.9% +/- 0.16% at the lumbar spine and 1.6% +/- 0.14% at the hip over the 24-month period. Despite wide variations in baseline calcium intake and changes in calcium intake, these measures were not significantly associated with changes in BMD or bone turnover. Even women whose total calcium intake was >1333 mg/d (the highest tertile of total calcium intake) showed a decline in BMD of almost 2%, similar to declines in the lower two tertiles of total calcium intake (<869 and 869-1333 mg/d, respectively). Increased calcium intake resulted in modest mean increases of approximately 200 mg/d. We were unable to demonstrate that increases of this magnitude or much greater (1 g/d) were protective against declines in BMD at any site, even in women who had the lowest calcium intake at baseline. In addition to adequate calcium intake, more effective therapy appears to be required when the therapeutic goal is to increase or maintain BMD.

Alendronate and osteoporosis

This is a review of the alendronate development program, starting with its pharmacological properties, current knowledge of its mode of action, preclinical studies of efficacy and bone safety. Then follows a brief review of the clinical studies, primarily the Phase III studies, which demonstrated increased bone density and provided preliminary data on fracture prevention, and the Fracture Intervention Trial studies, which demonstrated a reduction in the incidence of fractures of the spine, wrist, femur and all-site fractures. Alendronate and potentially other bisphosphonates can be useful drugs for the treatment and prevention of osteoporosis.

CHAPTER 29 – Epidemiology and Consequences of Osteoporotic Fractures

This chapter discusses the consequences and epidemiology of osteoporotic fractures. Hip and other fractures related to osteoporosis result in a greater number of hospital bed days than many other conditions among women, including myocardial infarction, diabetes, and breast cancer. Although hip fractures represent only about 9% of all osteoporotic fractures and outpatient services related to osteoporotic fractures, almost all hip fracture cases require hospitalization, and about half are discharged to nursing homes or other chronic care institutions in the United States. Although hip fractures account for a major share of economic costs, other fractures contribute substantially to health care costs. Recognizing risk factors for bone loss and risk factors for falls can help reduce the impact of factors contributing to fracture risk. Both bone marrow density (BMD) and fracture history have been used to categorize the severity of osteoporosis and fracture risk. Low bone mineral density (BMD; whether due to low peak BMD, bone loss, or both) is a major risk factor for fractures. Important risk factors for accelerated bone loss include corticosteroid use (losses increase with dose and duration), hypogonadism (including menopause), and immobilization (bedridden, casted fractures, and wheelchair-bound). Low body weight is a risk factor for bone loss and for hip fractures.