INTRODUCTION — Osteoporosis is a common disease that is characterized by low bone mass, microarchitectural disruption, and skeletal fragility, resulting in an increased risk of fragility fracture. In systematic reviews, the worldwide annual hip fracture rate in women ranged from <100 to nearly 600 per 100,000 and vertebral fracture rate from <100 to almost 1400 per 100,000, depending on the region [1,2].
Prevention of low bone mass and fractures using nonpharmacologic and pharmacologic therapies will be discussed here. The prevention of glucocorticoid-induced osteoporosis and the treatment of osteoporosis are reviewed separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Overview of the management of osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men".)
DEFINITIONS
●Osteoporosis – A clinical diagnosis of osteoporosis may be made in the presence of a fragility fracture, particularly at the spine, hip, wrist, humerus, rib, and pelvis, without measurement of bone mineral density (BMD). Fragility fractures are those occurring from a fall from a standing height or less, without major trauma such as a motor vehicle accident. Fractures at some skeletal sites, including the skull, cervical spine, hands, and feet, are not considered to be fragility fractures. Stress fractures are also not considered fragility fractures, as they are due to repetitive injury, often in individuals with otherwise healthy bones. (See "Overview of stress fractures".)
In the absence of a fragility fracture, BMD assessment by dual-energy x-ray absorptiometry (DXA) is the gold standard to diagnose osteoporosis, according to the classification of World Health Organization (WHO) [3]. BMD that is 2.5 standard deviations (SDs) or more below the mean BMD of a young-adult reference population, which is a T-score of -2.5 or less, qualifies for a diagnosis of osteoporosis, provided that other causes of low BMD have been ruled out.
As another means for diagnosis of osteoporosis, the National Bone Health Alliance recommends that a clinical diagnosis of osteoporosis may be made, in the United States, when the Fracture Risk Assessment Tool (FRAX) 10-year probability of major osteoporotic fracture is ≥20 percent or the 10-year probability of hip fracture is ≥3 percent [4,5].
●Low bone mass – Low bone mass (osteopenia) is defined as a T-score between -1.0 to -2.5.
Individuals with T-scores of ≤-2.5 have a high risk of fracture. However, there are more fractures in patients with a T-score between -1.0 and -2.5 because there are so many more patients in this category [6]. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men" and "Osteoporotic fracture risk assessment", section on 'Assessment of fracture risk'.)
WHY PREVENTION? — Bone strength reflects the integration of bone mineral density (BMD) and other properties of bone that are collectively called "bone quality" [7]. BMD in adults is determined by peak bone mass and subsequent bone loss. As BMD measured by dual-energy x-ray absorptiometry (DXA) decreases, fracture risk increases as a continuum, with no "fracture threshold." In one analysis, for every one standard deviation (SD) decrease in BMD at the hip, there was a 2.6-fold increase in the risk of hip fracture [8]. Thus, the prevention of low bone mass is directed to maximizing peak bone mass and minimizing the rate of bone loss, with the ultimate goals of maintaining bone strength and preventing fractures. Since most fractures occur with some impact on the bone, preventing falls is another important aspect of preventing fractures, especially in frail patients. (See "Falls: Prevention in community-dwelling older persons".)
The statement of Professor Charles E Dent that "senile osteoporosis is a pediatric disease" [9] illustrates the importance of achieving the maximum potential peak bone mass, thereby attenuating the effects of bone loss later in life. Preventing bone loss is preferable to treatment once it has occurred because degradation of bone microarchitecture associated with bone loss is largely irreversible. Treatment may stabilize or increase BMD and reduce the risk of fracture, but it is unlikely to fully restore bone quality and bone strength.
MAXIMIZING PEAK BONE MASS — Peak bone mass is the maximum bone mass achieved in life. Interventions to optimize peak bone mass and skeletal health should be directed toward a healthy lifestyle during the bone-forming years, particularly adolescence. These can be divided into categories of nutrition, physical activity, and other lifestyle factors. All children, and in particular, adolescents, should have adequate calcium and vitamin D intake (table 1), engage in regular physical activity, achieve normal body weight, and avoid smoking and alcohol use. Children 9 to 18 years of age should consume approximately 1300 mg of calcium daily, preferably from calcium-rich or calcium-fortified foods. Adequate vitamin D (600 international units) is necessary to promote intestinal calcium absorption. (See "Bone health and calcium requirements in adolescents".)
The timing of peak bone mass is not known with certainty but probably occurs in the third decade of life in most individuals, with differences in timing due to genetic, hormonal, and environmental variables, the skeletal site measured, and the method of bone mineral density (BMD) measurement [10]. Environmental factors include diet, exercise, habits (smoking, alcohol use), diseases, and medications. Patients with congenital disorders, such as osteogenesis imperfecta and cystic fibrosis, are now being more successfully managed in childhood, so that more survive and reach adulthood with low bone mass. Chronic inflammatory diseases during childhood and adolescence pose numerous threats to bone health, resulting in either immediate fragility fractures or subsequent fractures in adulthood caused by suboptimal peak bone mass. Peak bone mass acquisition is reviewed in detail separately. (See "Pathogenesis of osteoporosis", section on 'Peak bone mass acquisition'.)
Nutrition — Good nutrition from infancy through adolescence, with particular attention to adequate daily intake of calcium and vitamin D (table 1), is a key component in the attainment of maximum peak bone mass [11]. Most children should consume calcium-rich or calcium- and vitamin D-fortified foods to achieve this goal. Routine supplementation of calcium and vitamin D is not necessary for healthy growing children who consume a varied diet. For those unable to achieve adequate intake from diet, we suggest supplementation with calcium and vitamin D. However, the skeletal benefits of calcium and vitamin D supplements have been difficult to demonstrate in clinical trials, which may be due, in part, to the design of the trials. Most trials evaluated short-term supplementation in healthy children who did not have inadequate dietary intake of calcium and vitamin D. Supplementation is likely to benefit only those children with inadequate intake. In such children, longer-term follow-up is required to show a substantial benefit in bone mineralization and fracture prevention.
●In a meta-analysis of 19 randomized trials involving over 2800 healthy children, there was a small increase in total body mineral content in children randomly assigned to calcium supplementation (300 to 1200 mg daily for 0.7 to 7 years) compared with placebo (mean difference 0.14, 95% CI 0.01-0.27), but there were no differences in BMD at the femoral neck or lumbar spine [12].
●In some observational studies, serum vitamin D levels were positively associated with bone density in children and adolescents [13]. However, in a meta-analysis of six randomized trials involving over 800 healthy children and adolescents, there was no difference in total body bone mineral content or hip, forearm, or lumbar spine BMD in children randomly assigned to vitamin D supplementation or placebo [14].
●Some studies have shown that high consumption of carbonated soft drinks may impair bone acquisition [15] and increase fracture risk [16] in girls. However, other studies have shown that this effect is largely a matter of displacement of more nutritious beverages and that it may be reversed by taking the recommended daily intake of calcium [17,18].
●Anorexia nervosa, an increasingly common eating disorder in female adolescents, is associated with reduced BMD and increased fracture risk. (See "Anorexia nervosa: Endocrine complications and their management".)
●Other nutritional disorders known to impair bone accretion in adolescence include inflammatory bowel disease, celiac disease, and cystic fibrosis. (See "Metabolic bone disease in inflammatory bowel disease" and "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Musculoskeletal disorders' and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Metabolic bone disorders'.)
Physical activity — Observational, retrospective, and prospective randomized trials have demonstrated beneficial effects of exercise on bone accumulation during growth, with particular benefit from high-impact exercise [19-21]. On the other hand, excessive exercise can be harmful to skeletal health when it is accompanied by poor nutrition and reduced body fat, as seen in adolescents and young adults with female athlete triad (disordered eating, amenorrhea, osteoporosis) [22]. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations".)
Other lifestyle factors — Cigarette smoking has also been associated with decreased BMD and reduced cortical thickness in young men 18 to 20 years of age [23]. Cigarette smoking and excess alcohol intake should be discouraged [24-26]. In addition, administration of drugs that are known to be harmful to skeletal health, such as glucocorticoids and anticonvulsants, should be avoided or minimized in dose and duration.
Pharmacologic therapy — There is no role for pharmacologic therapy as a means to maximize peak bone mass, except in very special circumstances. As an example, pharmacologic doses of vitamin D for some children on anticonvulsant therapy or with celiac disease may be necessary to optimize skeletal health (see "Antiseizure medications and bone disease" and "Management of celiac disease in children", section on 'Screening and prevention of micronutrient deficiencies'). In addition, physiologic hormone replacement for deficiency states in children, such as growth hormone deficiency or hypogonadotropic hypogonadism, is essential to achieve normal peak bone mass. (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)" and "Treatment of growth hormone deficiency in children", section on 'Bone mass'.)
MINIMIZING BONE LOSS — Stabilizing bone mineral density (BMD) or reducing the rate of bone loss is the primary objective in the prevention of osteoporosis once peak bone mass has been attained. We agree with the Surgeon General's Report on Bone Health and Osteoporosis, which recommends a pyramid approach to the prevention and treatment of osteoporosis with a foundation of lifestyle changes that include nutrition, physical activity, and fall prevention; a second tier of addressing drugs and diseases associated with bone loss or osteoporosis; and a third tier of pharmacologic therapy [24].
Age-related bone loss begins soon after peak bone mass for either sex. In normal women, the annual rates of BMD loss appear to be highest during the one year before through two years after the final menstrual period (see "Epidemiology and etiology of premenopausal osteoporosis", section on 'Perimenopausal bone loss'). A longitudinal study of 620 men and women age 20 to 89 years showed a small bone loss (<0.4 percent per year) at the hip and spine in premenopausal women, with a tripling of the bone loss rate in the early postmenopausal years [27]. A typical rate of bone loss in early postmenopausal, estrogen-deficient women is probably approximately 0.5 to 1.5 percent per year, with a small percentage of women being "rapid bone losers" who may lose as much as 3 to 5 percent of bone mass per year. In men under age 50 years, there was a slow rate of bone loss at the hip, but not the spine, that continued throughout life [27]. Age-related bone loss in older women and men is approximately 0.5 to 1.0 percent per year.
Factors that influence the rate and magnitude of bone loss include concomitant diseases, hormone concentrations, age, body weight, calcium and vitamin D intake, physical activity, family history, alcohol consumption, and cigarette smoking. (See "Pathogenesis of osteoporosis" and "Osteoporotic fracture risk assessment".)
Reported rates of bone loss vary according to the type of study (cross-sectional versus longitudinal), skeletal site, skeletal compartment (trabecular versus cortical), type of measurement, ethnicity, sex, and other confounding factors [28-30].
Lifestyle measures — A healthy lifestyle should be encouraged in all adults in order to preserve BMD, bone microarchitecture, and bone strength. A healthy lifestyle includes regular weightbearing physical activity (30 minutes on most days of the week), adequate nutrition (protein, calcium, and vitamin D), smoking cessation, no or moderate alcohol intake, and fall prevention. In addition, affected patients should avoid, if possible, drugs that increase bone loss, such as glucocorticoids. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Calcium and vitamin D — We suggest 800 international units of vitamin D daily and 1200 mg elemental calcium (ideally from diet, plus supplements if needed) daily for most postmenopausal women [5,24,31]. Although the optimal intake (diet plus supplement) has not been clearly established in premenopausal women or in men, 1000 mg of calcium is generally suggested (table 1) [31]. The recommended dietary allowance of vitamin D for children 1 to 18 years and adults through age 70 years is 600 international units (15 mcg) and 800 international units (20 mcg) after age 71 years [31]. These suggestions are consistent with the 2010 Institute of Medicine (IOM) Dietary Reference Intakes for calcium and vitamin D [31]. The 2018 US Preventive Services Task Force (USPSTF) concluded that there was insufficient evidence to assess the benefits and harms of calcium and vitamin D supplementation for the primary prevention of fracture in premenopausal women and men [32]. They recommended against supplementation with ≤400 international units of vitamin D and ≤1000 mg of calcium for the primary prevention of fractures in postmenopausal women, and they concluded there was insufficient evidence to assess the benefits and harms at doses higher than these.
Calcium and vitamin D are necessary for normal skeletal homeostasis. Vitamin D enhances intestinal absorption of calcium and phosphate and is important for mineralization of bone, as well as optimal muscle function and balance. Low concentrations of vitamin D are associated with impaired calcium absorption, a negative calcium balance, and a compensatory rise in parathyroid hormone, which results in excessive bone resorption. While it is often difficult to distinguish effects of calcium from vitamin D in clinical trials, some meta-analyses have shown increases in BMD and a reduction in fracture risk in older patients supplemented with calcium and vitamin D. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Skeletal health outcomes' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Benefits of vitamin D supplementation'.)
Older persons confined indoors and other high-risk groups may have low serum 25-hydroxyvitamin D concentrations at the recommended intake level and may require higher intakes. Thus, in patients at very high risk for osteoporosis in whom there is a clinical suspicion that the usual doses of vitamin D are inadequate (malabsorption, decreasing bone mass), measurement of serum 25-hydroxyvitamin D may be necessary to ensure that supplementation is adequate, with the caveat that assay variability may be significant. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Optimal intake to prevent deficiency'.)
There is considerable controversy around the effects of calcium supplements on the risk of cardiovascular disease. This is discussed in detail separately. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Calcium'.)
If there is a history of nephrolithiasis, additional evaluation is required before making supplementation recommendations. (See "Kidney stones in adults: Prevention of recurrent kidney stones".)
Physical activity — Weightbearing physical activity is associated with small but significant improvement in BMD in premenopausal and postmenopausal women [33] and in men [34]. It may also improve muscle tone and reduce the risk of falls. The Surgeon General recommends a "minimum of 30 minutes of physical activity (such as brisk walking) on most, if not all, days of the week" [35]. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Exercise'.)
Other lifestyle factors — Meta-analyses have shown that cigarette smoking is associated with reduced BMD [36] and increased risk of fracture [37]. Every effort should be made to discourage initiation or continuation of cigarette smoking. Excess alcohol (more than two United States drinks or three United Kingdom units) is detrimental to skeletal health for many reasons [38], although moderate alcohol drinking has been associated with higher bone mass [39,40] and reduced fracture risk [41] in some studies. Moderation in alcohol intake is appropriate, although patients should not be advised to initiate alcohol drinking to improve skeletal health. (See "Overview of the risks and benefits of alcohol consumption", section on 'Osteoporosis'.)
Pharmacologic therapy to minimize bone loss
Candidates for pharmacologic therapy — For most patients with T-scores between -1.0 and -2.5 (low bone mass, osteopenia), we suggest not using pharmacologic therapy for prevention of bone loss. However, some patients with low bone mass are at high risk for fracture and are likely to benefit from pharmacologic therapy to reduce fracture risk. Management decisions should be individualized with consideration of all available clinical information, including estimation of fracture risk, as determined by a combination of BMD and clinical risk factors; the expected benefits and potential risks of drug therapy; and patient preferences.
Individuals with T-scores ≤-2.5 and those with prior osteoporotic fracture are at high risk of fracture and are likely to benefit from pharmacologic therapy to reduce fracture risk. For individuals with T-scores between -1.0 and -2.5, fracture risk can be calculated using the Fracture Risk Assessment Tool (FRAX). A reasonable cutpoint that may be cost effective in some settings is a 10-year probability of hip fracture or 10-year probability of major osteoporotic fracture of ≥3.0 or ≥20 percent, respectively. The Bone Health and Osteoporosis Foundation (BHOF, formerly the National Osteoporosis Foundation [NOF]) recommends pharmacologic therapy in patients with low bone mass (T-score between -1.0 and -2.5 at the femoral neck, total hip, or lumbar spine) if there is an estimated 10-year probability of hip fracture of ≥3 percent or of major osteoporotic fracture ≥20 percent [5]. Intervention thresholds in other countries vary based upon country-specific health economic data, such as fracture-related treatment costs and willingness-to-pay thresholds.
Guidelines for pharmacologic intervention based upon 10-year absolute fracture risk are reviewed in more detail separately. (See "Osteoporotic fracture risk assessment", section on 'Clinical application of fracture risk assessment' and "Overview of the management of osteoporosis in postmenopausal women", section on 'Patient selection' and "Treatment of osteoporosis in men", section on 'Candidates for therapy'.)
Glucocorticoid therapy is associated with an appreciable risk of bone loss, which is most pronounced in the first few months of use. In addition, glucocorticoids increase fracture risk, and fractures occur at higher BMD values than occur in postmenopausal osteoporosis. Prevention of glucocorticoid-induced osteoporosis is reviewed separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Choice of drug
●For postmenopausal women without osteoporosis who are candidates for and desire pharmacologic therapy for prevention of bone loss and/or fracture, we suggest an oral bisphosphonate or raloxifene, provided there is no contraindication. There are nonskeletal considerations with raloxifene that may play an important role in the selection of postmenopausal women for therapy: a reduction in breast cancer risk, an increase in thromboembolic events and hot flashes, and no apparent effect on heart disease or the endometrium.
•We prefer weekly alendronate or risedronate to other bisphosphonates because of their efficacy, favorable cost, and the availability of long-term safety data. Limitations of oral bisphosphonates include the complex dosing regimen and poor long-term adherence to therapy. Intravenous (IV) zoledronic acid is an option for some women, particularly those who are not able to take oral bisphosphonates due to intolerance or a contraindication, with the benefits of a long dosing interval (two years) and assured long-term skeletal effects.
•Raloxifene inhibits bone resorption and reduces the risk of vertebral fracture and is our selective estrogen receptor modulator (SERM) of choice because it has eight-year safety and efficacy data and also reduces the risk of breast cancer.
●Although we do not consider estrogen a first-line option for the prevention of osteoporosis because of concerns of adverse effects, women who seek hormone therapy for menopausal symptoms in their late 40s or early 50s will have the additional benefit of a reduced risk of bone loss and fracture [42]. The benefit/risk profile of hormone replacement therapy may vary for women based upon their time since menopause. This topic is reviewed elsewhere. (See "Menopausal hormone therapy: Benefits and risks", section on 'Estimates of risk in women 50 to 59 years'.)
●There are no US Food and Drug Administration (FDA)-approved medications for prevention of osteoporosis in men. However, for men who are candidates for and desire pharmacologic therapy for prevention of osteoporosis, we suggest bisphosphonates (alendronate or risedronate). Hypogonadism is a risk factor for osteoporosis in men, and testosterone replacement in hypogonadal men has beneficial effects on BMD. This topic is reviewed elsewhere. (See "Testosterone treatment of male hypogonadism", section on 'Bone density' and "Treatment of osteoporosis in men", section on 'Hypogonadism'.)
Efficacy — Drugs that are efficacious in the prevention of bone loss include estrogen, alendronate, risedronate, ibandronate, zoledronic acid, raloxifene, and combination bazedoxifene-conjugated equine estrogen (CEE) (table 2).
Estrogen — Estrogen is not currently recommended as a first-line agent for the management of osteoporosis, but if a decision has been made to use estrogen for the treatment of menopausal symptoms, then reductions in bone loss and fracture risk are additional benefits.
The Women's Health Initiative (WHI) showed that oral CEEs 0.625 mg/day, with or without medroxyprogesterone acetate (MPA) 2.5 mg/day, reduced the risk of hip, vertebral, and other fractures in healthy, postmenopausal women (mean age 63 to 64 years at beginning of study) not selected on the basis of low BMD [43,44]. However, it was determined that in the WHI population, the risks of estrogen exceeded the benefits, even in women at high risk for fracture [45]. Whether the results and conclusions of the WHI apply to younger postmenopausal women taking estrogen in other doses, formulations, or modes of administration is not known. This topic is discussed in greater detail elsewhere. (See "Menopausal hormone therapy: Benefits and risks", section on 'Estimates of risk in women 50 to 59 years'.)
Doses of estrogen lower than that used in the WHI, or nonoral delivery systems, including a low-dose patch containing 0.014 mg of estradiol that is adequate for hot flash relief in some women, have been shown to have beneficial skeletal benefits [46-48]. We typically start women on transdermal preparations as they contain 17-beta estradiol, the main estrogen the ovary secretes prior to menopause, and because transdermal administration is associated with a lower risk of venous thromboembolism and stroke than oral administration. However, the baseline risk of both complications is very low in otherwise healthy, young, postmenopausal women. If a patient prefers an oral preparation over a transdermal one (cost or personal preference), we typically prescribe oral 17-beta estradiol. If an estrogen is used for any reason, it should be taken in the lowest possible dose for the shortest period of time needed to achieve the goals of treatment. (See "Treatment of menopausal symptoms with hormone therapy" and "Menopausal hormone therapy in the prevention and treatment of osteoporosis".)
Bisphosphonates — Currently available bisphosphonates for the prevention of postmenopausal osteoporosis are alendronate (5 mg/day or 35 mg/week), risedronate (5 mg/day or 35 mg/week), ibandronate (150 mg/month), and zoledronic acid (5 mg IV once every 2 years). If a bisphosphonate is chosen for preventive therapy, we prefer weekly alendronate or risedronate to other bisphosphonates because of their efficacy, favorable cost, and the availability of long-term safety data. The prevention dose with alendronate is one-half the dose for treatment, while the prevention and treatment doses are the same for the others. For prevention versus treatment of osteoporosis with zoledronic acid, the interval between doses is longer (every two years versus once yearly). Ibandronate is also approved for 2.5 mg/day, but this dosing form is not available.
Medications in this class of potent antiresorptive agents have been shown to increase BMD in young and older postmenopausal women and to reduce fracture risk in older postmenopausal women [49-51]. The studies evaluating bisphosphonates for prevention of bone loss in ambulatory women who are one to two years postmenopausal were not powered to evaluate fracture reduction. Bisphosphonates for the treatment of osteoporosis in women and men are reviewed separately. (See "Bisphosphonate therapy for the treatment of osteoporosis" and "Treatment of osteoporosis in men", section on 'Bisphosphonates'.)
Alendronate — In addition to its efficacy in the treatment of osteoporosis in postmenopausal women, alendronate is useful for the prevention of osteoporosis [52-56]. As an example, in a double-blind, randomized trial of 447 women who had been menopausal for 6 to 36 months, alendronate for three years at 5, 10, and 20 mg/day increased BMD at the lumbar spine, femoral neck, and trochanter by 1 to 4 percent [52]. In comparison, those receiving placebo lost 2 to 4 percent at these sites. The protective effect of alendronate disappeared relatively rapidly after cessation of therapy [53].
A second randomized study found similar efficacy (3.5 percent increase in BMD at the lumbar spine and 1.9 percent increase at the hip) with the 5 mg dose of alendronate administered to postmenopausal women under the age of 60 years for two years [54]. In a follow-up study of this cohort for four [55] and six years [56], the positive effects of continued therapy on BMD were maintained [55]. This dose was as, or perhaps slightly less, beneficial than estrogen-progestin therapy. Women receiving alendronate during years 1 and 2 who then received placebo in years 3 and 4 had the expected fall in BMD.
These studies did not show a significant reduction in fracture rate.
Risedronate — Risedronate is also effective for prevention of bone loss in early postmenopausal women [50,57,58]. As an example, in a two-year trial of risedronate (5 mg daily) versus placebo in 111 postmenopausal women with normal BMD, there was a mean increase in BMD of the lumbar spine (1.4 percent) in the risedronate group versus a decline (4.3 percent) in the placebo group [57]. This study did not have power to show fracture prevention.
Ibandronate — Daily oral ibandronate has been shown to improve BMD in postmenopausal women without osteoporosis, as illustrated by the findings of a 24-month trial of ibandronate (2.5 mg daily) versus placebo in 653 postmenopausal women without osteoporosis (baseline T-score better than -2.5) [59]. Daily oral ibandronate increased BMD at the lumbar spine and hip (3.1 and 1.8 percent, respectively, compared with placebo).
Zoledronic acid — In a six-year trial of zoledronic acid (5 mg) versus normal saline, each administered intravenously every 18 months, in 2000 postmenopausal women (mean age 71.5 years) with total hip or femoral neck T-score of -1.0 to -2.5, the risk of fragility fractures was reduced in the zoledronic acid group (22.1 versus 38.5 fractures per 1000 woman-years, hazard ratio [HR] 0.63, 95% CI 0.50-0.79) [60]. Approximately 40 percent of women had a baseline T-score of -2.5 or lower (at a different skeletal site) or met FRAX criteria for high risk of fracture (baseline risk of hip fracture ≥3 percent or of major osteoporotic fracture ≥20 percent). The reduction in fracture risk with zoledronic acid remained statistically significant even after exclusion of participants with baseline T-score <-2.5 at one or more skeletal sites, a clinical diagnosis of osteoporosis (based on history of prior nonvertebral fracture after age 45 years), or high fracture probability by FRAX.
In a two-year trial of zoledronic acid (5 mg IV once at baseline or yearly for two years) versus placebo in 581 postmenopausal women with low bone mass, patients randomly assigned to a single zoledronic acid infusion had significant increases in lumbar spine and total hip BMD (approximately 3 percent) [61]. The study was not powered to detect differences in fracture risk.
General principles and adverse effects — There are several general principles for the use of the bisphosphonates. Detailed instructions for correct oral administration are recommended to maximize absorption and minimize the risk of esophageal adverse effects. After three to five years of bisphosphonate therapy, patients should be revaluated to determine whether the benefits of continuing therapy outweigh the risks. These general principles and adverse effects are reviewed in detail elsewhere. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Practical management issues' and "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Duration of therapy' and "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Risks specific to oral bisphosphonates'.)
Selective estrogen receptor modulators (SERMs) — Raloxifene (60 mg/day) and combination bazedoxifene-CEE (20 mg/0.45 mg) are available in the United States for the prevention of postmenopausal osteoporosis. Raloxifene and bazedoxifene (as a single agent) are available in other countries, including Europe and Japan. If a SERM is chosen for preventive therapy, raloxifene is our SERM of choice because it has eight-year safety and efficacy data and also reduces the risk of breast cancer.
Raloxifene has been shown to increase BMD and reduce the risk of vertebral fractures but not nonvertebral fractures [62]. Important nonskeletal considerations with raloxifene include reduction in breast cancer risk, increased risk of thromboembolic events, and hot flashes. There is no apparent effect on heart disease or the endometrium. Conjugated estrogens and bazedoxifene individually have been shown to prevent vertebral fracture. The combination of bazedoxifene-CEE has been shown to improve bone density [63]; however, there are no fracture prevention data for combination therapy. In clinical trials, the combination formulation improved indices of vaginal atrophy and reduced the daily number of hot flushes. Its effect on breast cancer is unknown. SERMs for osteoporosis are discussed in detail elsewhere. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoporosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Osteoporosis (The Basics)" and "Patient education: Calcium and vitamin D for bone health (The Basics)" and "Patient education: Medicines for osteoporosis (The Basics)")
●Beyond the Basics topics (see "Patient education: Osteoporosis prevention and treatment (Beyond the Basics)" and "Patient education: Calcium and vitamin D for bone health (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS — Osteoporosis is a preventable disease, not an inevitable consequence of aging. The management of skeletal health should be directed toward maximizing peak bone mass and minimizing bone loss that occurs with aging and declining sex hormone levels. In general, healthy lifestyle measures should be encouraged for all individuals to preserve bone mineral density (BMD), bone microarchitecture, and bone strength.
●Healthy lifestyle measures for maximizing peak bone mass during the bone-forming years include adequate calcium and vitamin D intake, physical activity (although not excessive), and avoidance of cigarette smoking and alcohol. Recommended calcium intake for children and adolescents 9 to 18 years old is 1300 mg daily, preferably from calcium-rich or calcium-supplemented foods. Adequate vitamin D (600 international units) is necessary to promote intestinal calcium absorption (table 1). Routine supplementation of calcium and vitamin D is not necessary for healthy, growing children who consume a varied diet. For children and adolescents who have very low intakes of dietary calcium (<600 mg/day) and vitamin D (<400 international units/day), we suggest supplementation (Grade 2B). (See 'Maximizing peak bone mass' above and "Bone health and calcium requirements in adolescents" and "Vitamin D insufficiency and deficiency in children and adolescents".)
●Similar healthy lifestyle measures for prevention of subsequent bone loss in adults include regular weightbearing exercise, adequate calcium and vitamin D intake, avoidance of cigarette smoking, and limitation of alcohol to an average of no more than two drinks daily. For postmenopausal women and men over 70 years old, the recommended total calcium intake is approximately 1200 mg daily (total diet plus supplements, if needed) (table 1). The recommended dietary allowance of vitamin D for adults through age 70 years is 600 international units (15 mcg) and 800 international units (20 mcg) after age 71 years. However, older persons confined indoors and other high-risk groups may have low serum 25-hydroxyvitamin D concentrations and may require higher intakes. (See 'Minimizing bone loss' above.)
For older adults with inadequate dietary calcium and vitamin D intake, we suggest calcium and vitamin D supplementation (Grade 2B). (See 'Calcium and vitamin D' above and "Calcium and vitamin D supplementation in osteoporosis".)
●For the majority of adults who do not have osteoporosis and are not at high risk of fracture, we suggest not using pharmacologic therapy for prevention of bone loss (Grade 2B). (See 'Candidates for pharmacologic therapy' above.)
Since pharmacologic therapy has costs and possible risks, only patients at high risk of fracture are generally considered candidates for preventive drugs. Thus, patients with low bone mass (T-score between -1.0 and -2.5) should be considered for pharmacologic intervention if fracture risk is high, as determined by a combination of BMD and clinical risk factors. Fracture risk can be calculated using the Fracture Risk Assessment Tool (FRAX) or other fracture risk calculators. A reasonable cutpoint that may be cost effective in some settings is a 10-year probability of hip fracture or major osteoporotic fracture of ≥3 or ≥20 percent, respectively. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Patient selection' and "Treatment of osteoporosis in men", section on 'Candidates for therapy'.)
●For postmenopausal women who are candidates for and desire pharmacologic therapy for prevention of osteoporosis, we suggest bisphosphonates or raloxifene as first-line choices (Grade 2B). We prefer weekly alendronate or risedronate to other bisphosphonates because of their efficacy, favorable cost, and the availability of long-term safety data (table 2). Intravenous (IV) zoledronic acid is an alternative option for some women, especially those who are not able to take oral bisphosphonates due to intolerance or a contraindication, and those who prefer the long dosing interval and long-term skeletal benefit. There are nonskeletal considerations with raloxifene that may play an important role in the selection of postmenopausal women for therapy: a reduction in breast cancer risk, an increase in thromboembolic events and hot flashes, and no apparent effect on heart disease or the endometrium. (See 'Choice of drug' above.)
There are no US Food and Drug Administration (FDA)-approved medications for prevention of osteoporosis in men. However, for men who are candidates for and desire pharmacologic therapy for prevention of osteoporosis, we suggest bisphosphonates (Grade 2B). We prefer weekly alendronate or risedronate to other bisphosphonates because of their efficacy, favorable cost, and the availability of long-term safety data. (See 'Choice of drug' above and "Treatment of osteoporosis in men", section on 'Choice of therapy'.)
●The prevention of glucocorticoid-induced bone loss is reviewed separately. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
