Bisphosphonates and osteonecrosis of the jaw.
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Bone Density Conservation Agents↗
Biomedical subjects
Michael R McClung
Publications and source records attributed to Michael R McClung.
Bone mineral density in women aged 25-35 years receiving depot medroxyprogesterone acetate: recovery following discontinuation.
INTRODUCTION: This 7-year, prospective, matched-cohort, clinical study evaluated the effects of intramuscular depot medroxyprogesterone acetate (DMPA) (150 mg/mL) on bone mineral density (BMD) in women aged 25-35 years. METHODS: Bone mineral density changes in new DMPA-IM users (n=248) were compared with those in women using nonhormonal contraception (n=360) for up to 240 weeks of treatment and 96 weeks of posttreatment follow-up (in subjects receiving >or=1 dose). RESULTS: At week 240 of treatment, mean percentage changes from baseline in DMPA-IM vs. nonhormonal subjects were: -5.16% (n=21) vs. +0.19% (n=65), total hip (p<.001); -5.38% (n=33) vs. +0.43% (n=105), lumbar spine (p<.001). At week 96 posttreatment, these values were: -0.20% (n=25) vs. +0.84% (n=43), total hip (p=.047); -1.19% (n=41) vs. +0.47% (n=66), lumbar spine (p=.017). CONCLUSIONS: These results show BMD declines during DMPA-IM use; following discontinuation, significant increases in BMD occur through 96 weeks posttreatment.
Adult↗
Denosumab in postmenopausal women with low bone mineral density.
BACKGROUND: Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162) binds RANKL with high affinity and specificity and inhibits RANKL action. METHODS: The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of -1.8 to -4.0 at the lumbar spine or -1.8 to -3.5 at the proximal femur). Subjects were randomly assigned to receive denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open-label oral alendronate once weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase. RESULTS: Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo), and at the distal third of the radius of 0.4 to 1.3 percent (as compared with decreases of 0.5 percent with alendronate and 2.0 percent with placebo). Near-maximal reductions in mean levels of serum C-telopeptide from baseline were evident three days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent. CONCLUSIONS: In postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis. (ClinicalTrials.gov number, NCT00043186.).
Alendronate↗
Do current management strategies and guidelines adequately address fracture risk?
Deciding which patients are appropriate candidates for our effective osteoporosis therapies is a clinical challenge. Current guidelines for treating postmenopausal osteoporosis are based primarily on bone mineral density (BMD) measurements. There is consensus that postmenopausal women with osteoporosis, as defined by T-scores of -2.5 and lower, are at high risk of fracture and are candidates for therapy. However, many older adults without osteoporosis are at increased risk for fracture, and most fractures occur in women with higher T-scores. Current BMD-based guidelines are inconsistent regarding recommendations for treating women without osteoporosis. Fracture risk assessment is improved by combining BMD and other important risk factors for fracture, especially greater age and history of prior fracture. Strategies to estimate absolute fracture risk in individual patients are being developed. Revised treatment guidelines, based upon thresholds of absolute fracture risk, will provide the opportunity to identify and to treat those women who will most benefit from our therapies.
Age Factors↗
Inhibition of RANKL as a treatment for osteoporosis: preclinical and early clinical studies.
Osteoporosis and several other bone disorders occur when there is an imbalance between the resorption and formation components of bone remodeling activity. Therapies available for some of these conditions modulate the activity of osteoclasts and/or osteoblasts. The recent discoveries of receptor activator of NF-kappaB ligand (RANKL), an endogenous activator of osteoclastogenenesis and osteoclast activity and its inhibitor, osteoprotegerin (OPG) as pivotal regulatory factors in the pathogenesis of bone diseases like osteoporosis provide unique targets for therapeutic agents. In laboratory animals and now in humans, administering forms of OPG markedly inhibits osteoclast activity and improves bone strength, documenting that the strategy of inhibiting RANKL activity has therapeutic promise. A highly specific, fully human antibody against RANKL has been produced (denosumab) that in early studies in humans reduces bone turnover and improves bone density. Attributes of denosumab in these clinical studies include a very rapid onset of action, sustained effects for several months after a single injection, and good tolerability. These results provide the basis for studies evaluating the effectiveness of denosumab in several clinical conditions characterized by increased osteoclastic activity.
Animals↗
A new concept for bisphosphonate therapy: a rationale for the development of monthly oral dosing of ibandronate.
Oral daily and weekly bisphosphonates represent the current mainstay of treatment for postmenopausal osteoporosis (PMO). However, the inconvenience of frequent dosing is known to negatively affect adherence to therapy in the long term. This has prompted the development of convenient oral bisphosphonate regimens that feature simple, less frequent dosing schedules. Such regimens require high potency agents, which can be given at low effective doses and that also have good tolerability. Ibandronate is a potent, nitrogen-containing bisphosphonate with proven efficacy when given intermittently to estrogen-depleted beagle dogs, rats and cynomolgus monkeys. Clinically, a pivotal prospective study has established that oral ibandronate has significant vertebral fracture efficacy in PMO, whether given daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 months; extended between-dose interval>2 months). Both oral regimens were well tolerated, which is noteworthy as patients with a history of gastrointestinal (GI) disturbance were not specifically excluded. As a result of these findings, a large, multinational, randomized, double-blind study (Monthly Oral iBandronate In LadiEs: MOBILE) is currently exploring the non-inferiority of once-monthly oral ibandronate (100 or 150 mg) to the oral daily ibandronate (2.5 mg) regimen with proven anti-fracture efficacy, in terms of lumbar spine bone mineral density (BMD) change. As with the trials investigating the weekly administration of other bisphosphonates, vertebral fracture efficacy will be inferred if the study demonstrates the non-inferiority of once-monthly ibandronate to the proven oral daily regimen in terms of spinal BMD change. The availability of this once-monthly ibandronate regimen is expected to offer benefits in terms of convenience (by having to follow dosing recommendations once a month vs. once daily or weekly) and potentially tolerability (by reducing the potential for upper GI irritation that can result from frequent, repeated exposure). Greater convenience and tolerability may enhance the therapy adherence and, hence, improve long-term therapeutic outcomes in PMO.
Administration, Oral↗
Osteopenia: to treat or not to treat?
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Aged↗
Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use.
All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide [recombinant human PTH(1-34)], represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive. Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores < or = 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity. Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (< or =1000 U/d). Monitoring of serum calcium may be safely limited to measurement after 1 month of treatment; mild hypercalcemia may be treated by withdrawing dietary calcium supplements, reducing the dosing frequency of PTH, or both. At present, concurrent therapy with antiresorptive therapy, particularly bisphosphonates, should be avoided, although sequential therapy with such agents may consolidate the beneficial effects upon the skeleton after PTH is discontinued.
Aged↗
Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study.
UNLABELLED: Once-monthly (50/50, 100, and 150 mg) and daily (2.5 mg; 3-year vertebral fracture risk reduction: 52%) oral ibandronate regimens were compared in 1609 women with postmenopausal osteoporosis. At least equivalent efficacy and similar safety and tolerability were shown after 1 year. INTRODUCTION: Suboptimal adherence to daily and weekly oral bisphosphonates can potentially compromise therapeutic outcomes in postmenopausal osteoporosis. Although yet to be prospectively shown in osteoporosis, evidence from randomized clinical trials in several other chronic conditions shows that reducing dosing frequency enhances therapeutic adherence. Ibandronate is a new and potent bisphosphonate with antifracture efficacy proven for daily administration and also intermittent administration with a dose-free interval of >2 months. This report presents comparative data on the efficacy and safety of monthly and daily oral ibandronate regimens. MATERIALS AND METHODS: MOBILE is a 2-year, randomized, double-blind, phase III, noninferiority trial. A total of 1609 women with postmenopausal osteoporosis were assigned to one of four oral ibandronate regimens: 2.5 mg daily, 50 mg/50 mg monthly (single doses, consecutive days), 100 mg monthly, or 150 mg monthly. RESULTS: After 1 year, lumbar spine BMD increased by 3.9%, 4.3%, 4.1%, and 4.9% in the 2.5, 50 /50, 100, and 150 mg arms, respectively. All monthly regimens were proven noninferior, and the 150 mg regimen superior, to the daily regimen. All monthly regimens produced similar hip BMD gains, which were larger than those with the daily regimen. All regimens similarly decreased serum levels of C-telopeptide, a biochemical marker of bone resorption. Compared with the daily regimen, a significantly larger proportion of women receiving the 100 and 150 mg monthly regimens achieved predefined threshold levels for percent change from baseline in lumbar spine (6%) or total hip BMD (3%). All regimens were similarly well tolerated. CONCLUSIONS: Monthly ibandronate is at least as effective and well tolerated as the currently approved daily ibandronate regimen in postmenopausal osteoporosis.
Absorptiometry, Photon↗
The relationship between bone mineral density and fracture risk.
Osteoporosis is a disorder characterized by low bone density and impaired bone strength which is an important risk factor for fracture in older adults. The diagnosis of osteoporosis in postmenopausal women is now based on bone density testing by dual energy x-ray absorptiometry but not other methodologies. However, a specific but arbitrary diagnostic threshold must be distinguished from a strategy to assess fracture risk. In untreated postmenopausal women and older men, bone density is an important, but not the only, determinant for fracture risk. Combining bone density measurements with other independent and validated risk factors for fracture provides a much more accurate assessment of an individual patient's risk for fracture than does bone density alone. The most important of these other risk factors are age and prior fracture history. Clinical guidelines will move away from recommending treatment at specific T scores toward intervention thresholds based on absolute fracture risk. By basing who to treat on fracture probability, therapy can be targeted to those patients who would receive the greatest benefit.
Absorptiometry, Photon↗
Osteoporosis in men: epidemiology, diagnosis, prevention, and treatment.
BACKGROUND: Osteoporosis and fragility fractures in men account for substantial health care expenditures and decreased quality of life. OBJECTIVE: This article reviews the most current information about the epidemiology, diagnosis, prevention, and treatment of osteoporosis in men. METHODS: Relevant literature was identified through a search of MEDLINE (1966-June 2003) limited to English-language studies in men. The search terms included fractures, bone density, or osteoporosis plus either epidemiology, diagnosis, prevention, control, or therapy. Additional search terms included specific subtopics (eg, bisphosphonates, calcium, exercise, parathyroid hormone). The authors contributed additional relevant publications. RESULTS: Morbidity after fragility fracture is at least as high in men as in women, and the rate of fracture-related mortality 1 year hip fracture is approximately double in men compared with women. The bioavailable fraction of testosterone slowly declines into the ninth decade in men. There is evidence that the effect of estrogen on bone is greater than that of testosterone in men. Diagnosing osteoporosis in men is complicated by a lack of consensus on how it should be defined. Significant risk factors for osteoporosis or fracture include low bone mineral density, previous fragility fracture, maternal history of fracture, marked hypogonadism, smoking, heavy alcohol intake or alcoholism, low calcium intake, low body mass or body mass index, low physical activity, use of bone-resorbing medication such as glucocorticoids, and the presence of such conditions as hyperthyroidism, hyperparathyroidism, and hypercalciuria. Prevention is paramount and should begin in childhood. During adulthood, calcium (1000-1500 mg/d), vitamin D (400-800 IU/d), and adequate physical activity play crucial preventive roles. When treatment is indicated, the bisphosphonates are the first choice, whereas there is less support for the use of calcitonin or androgen therapy. Parathyroid hormone (1-34) is a promising anabolic therapy. There is also strong evidence for the use of bisphosphonates for the treatment of glucocorticoid-induced osteoporosis.
Androgens↗
Safety and efficacy of risedronate in reducing fracture risk in osteoporotic women aged 80 and older: implications for the use of antiresorptive agents in the old and oldest old.
OBJECTIVES: To determine the efficacy of risedronate in reducing vertebral fracture risk in women aged 80 and older with osteoporosis. DESIGN: Pooled analysis of data from three randomized, double-blind, controlled, 3-year-fracture-endpoint trials conducted from November 1993 to April 1998: Hip Intervention Program (HIP), Vertebral Efficacy with Risedronate Therapy-Multinational (VERT-MN), and VERT-North America (NA). SETTING: Office-based practices, research centers, and osteoporosis clinics in Europe, North America, and Australia. PARTICIPANTS: Osteoporotic (femoral neck bone mineral density T-score < -2.5 standard deviations or at least one prevalent vertebral fracture) women aged 80 and older. INTERVENTION: Patients received placebo (n=688) or risedronate 5 mg/d (n=704) for up to 3 years. All patients received 1,000 mg/d calcium and, if baseline levels were low, up to 500 IU/d vitamin D. MEASUREMENTS: Cumulative incidence of new vertebral fractures. RESULTS: After 1 year, the risk of new vertebral fractures in the risedronate group was 81% lower than with placebo (95% confidence interval=60-91%; P<.001). The number of women who needed to be treated to prevent one new vertebral fracture after 1 year was 12. This early onset of efficacy was consistent across the clinical programs, and antifracture efficacy was confirmed over 3 years. Risedronate was well tolerated, with a safety profile comparable with that of placebo. CONCLUSION: These findings provide the first evidence that, even in the very old, reducing bone resorption rate remains an effective treatment strategy for osteoporosis. Because each therapeutic agent used for the treatment of osteoporosis may have unique characteristics, the observations made in this study should not be assumed to apply to other bisphosphonates.
Aged↗
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.
Alendronate↗
Official positions of the international society for clinical densitometry.
The International Society for Clinical Densitometry (ISCD) periodically holds Position Development Conferences for the purpose of establishing standards and guidelines for indications, acquisition, and interpretation of bone density tests. Topics are selected for consideration by the ISCD Scientific Advisory Committee, reviewed by scientific working groups, and presented to an international panel of experts. Topic categories addressed to date include indications for bone density testing, selection of reference databases for T-scores and Z-scores, clinical applications for central and peripheral bone densitometry, serial bone density testing, instrument precision assessment, phantom scanning and calibration testing, requirements for a bone density report, nomenclature, and diagnosis of osteoporosis in postmenopausal women, premenopausal women, men, and children. After an open session for public comment and discussion, the panel convenes for consideration of each topic and makes recommendations for positions to the ISCD Board of Directors. Recommendations that are accepted become the Official Positions of the ISCD. This Special Report summarizes the methodology of the ISCD Position Development Conferences and presents selected Official Positions of general interest.
Absorptiometry, Photon↗
Oral daily ibandronate prevents bone loss in early postmenopausal women without osteoporosis.
UNLABELLED: Oral daily ibandronate was investigated for the prevention of bone loss in postmenopausal women without osteoporosis (n = 653). BMD at the lumbar spine and hip were significantly increased (3.1% and 1.8%, respectively; p < or = 0.0001 versus placebo) with 2.5 mg ibandronate after 24 months. Oral ibandronate is a promising option for the prevention of postmenopausal bone loss. INTRODUCTION: Further strategies to manage patients most at risk from developing postmenopausal osteoporosis are required. The objectives of this multicenter, double-blind, randomized, placebo-controlled study were to examine the efficacy, tolerability, and optimal dose of oral daily ibandronate in the prevention of bone loss in postmenopausal women. MATERIALS AND METHODS: In total, 653 women (mean bone mineral density [BMD] T-score > -2.5 at the lumbar spine), who had been postmenopausal for at least 1 year, were allocated to one of four strata based on time since menopause and baseline lumbar spine BMD. Women were randomized to receive calcium (500 mg daily) plus either placebo (n = 162) or ibandronate 0.5 mg (n = 162), 1 mg (n = 166), or 2.5 mg (n = 163) as once-daily oral treatment for 2 years. The primary endpoint was the mean percent change in lumbar spine BMD with ibandronate versus placebo. RESULTS AND CONCLUSIONS: After 2 years, oral daily ibandronate produced a dose-related and sustained maintenance or increase in BMD at the lumbar spine and hip (total hip, femoral neck, trochanter), together with a dose-related reduction in the rate of bone turnover. The greatest nominal increases in spinal and hip BMD were observed with the 2.5-mg dose, which produced statistically significant BMD gains compared with placebo at 6 months and all subsequent time-points at the spine and hip (3.1% and 1.8% increase in lumbar spine and total hip BMD, respectively, versus placebo; p < or = 0.0001 after 24 months). Oral daily ibandronate was well tolerated with an incidence of upper gastrointestinal adverse events similar to placebo. No safety concerns were identified. In summary, oral daily ibandronate 2.5 mg decreases bone turnover, preserves or increases BMD in the spine and proximal femur, and is well tolerated. Oral ibandronate provides a promising option for the prevention of bone loss in postmenopausal women.
Aged↗
Bisphosphonates.
Bisphosphonates now occupy a prominent position among therapeutic options for the prevention and treatment of various forms of osteoporosis. Their clinical profile of bone-specific efficacy, rapid response, protection from both spine and hip fractures in patients with osteoporosis, and excellent tolerability is all that can be expected of an anti-remodeling drug. Even in the era of anabolic agents, bisphosphonates will continue to be important treatment options. It is not possible to compare or contrast the clinical effectiveness of the various bisphosphonates on the basis of existing data. Despite marked differences in the in vitro potency of drugs, the clinical responses to each of the bisphosphonates discussed above are similar. New bisphosphonates may not be more effective but will provide different tolerability profiles and different routes of administration, thereby increasing the number of patients in whom bisphosphonates can be used. Having these effective agents challenges clinicians to identify the most appropriate patients for bisphosphonate use and to develop strategies to improve acceptance of and adherence to these useful agents.
Aged↗
Pathogenesis of osteoporotic hip fractures.
Osteoporosis is characterized late in the course of the disease by an increased risk of fracture, particularly in the elderly. It occurs in both sexes, affecting approximately 8 million women and 2 million men aged > or = 50 years (1). While low bone density is a predictor of fractures, it is not the only determinant of fracture risk. Other factors include advanced age, altered bone quality, a personal or family history of falls, frailty, poor eyesight, debilitating diseases, and high bone turnover. A diet with sufficient calcium and vitamin D is important to minimize bone loss and, along with regular exercise, to maintain muscle strength. Bisphosphonates have been shown to reduce the risk of hip fracture. For elderly patients, the use of hip protectors may be used as a treatment of last resort. Regardless of the age of the patient, individual patient risk factors must be considered to target appropriate treatment and prevent fracture.
Accidental Falls↗
The menopause and HRT. Prevention and management of osteoporosis.
Post-menopausal osteoporosis is characterized by increased fracture risk due to deficiencies in both the quantity and quality of bone. Assessing fracture risk involves combining clinical risk factors, including fall risks, with bone density testing. Treatment strategies are aimed at reducing fracture risk. General nutritional and lifestyle measures are appropriate for all women. Drug treatment is most clearly indicated in post-menopausal women at high current fracture risk. Treatment should also be considered for women at intermediate fracture risk, including those who have both low bone density and other risk factors for fracture. Whether there is practical clinical value in treating low-risk patients is much less clear. Non-pharmacological approaches addressing the consequences of fractures are integral parts of a comprehensive treatment programme. Reducing both the frequency and the effects of falls complements the efforts of treating osteoporosis to reduce the incidence of fractures and their important clinical consequences.
Calcitonin↗