CLINICAL OBSTETRICS AND GYNECOLOGY Volume 51, Number 3, 556563 r 2008, Lippincott Williams & Wilkins

Osteoporosis Prevention and Management An Evidence-based Review

MICHAEL KLEEREKOPER, MD, MACE,* and DEBORAH T. GOLD, PhDw *Department of Internal Medicine, St. Joseph Mercy Hospital, Ann Arbor, and Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, Michigan; w Departments of Psychiatry & Behavioral Sciences, Sociology, and Psychology & Neuroscience, Duke University Medical Center, Durham, North Carolina

Abstract: Evidence-based guidelines that have been prepared by many professional organizations aimed at assisting the clinician in the initial evaluation of postmenopausal women who should be considered for bone mineral density evaluation by dual-energy x-ray absorptiometry; history, physical examination, and laboratory testing in those women being considered for pharmacologic intervention; and monitoring and management of women for whom therapy is prescribed are discussed. Key words: osteoporosis, peak adult bone mass, menopause

Osteoporosis is defined as a systemic skeletal disorder characterized by compromised bone strength predisposing to an
Correspondence: Michael Kleerekoper, MD, MACE, Department of Internal Medicine, St. Joseph Mercy Hospital, 5333 McAuley Drive, RHB #3009, Ypsilanti, MI 48197. E-mail: kleerekm@trinity-health.org
CLINICAL OBSTETRICS AND GYNECOLOGY /

increased risk of fracture.1 Before fracture, osteoporosis can only be diagnosed on the basis of a bone mineral density (BMD) t score <2.5 measured by dualenergy x-ray absorptiometry (DXA) at the radius, spine, or proximal femur. An osteoporosis-related fracture traditionally is defined as a fracture after trauma that is equal to or less than a fall from a standing height. All pharmacologic therapies approved by the Food and Drug Administration (FDA) in the United States have had to demonstrate significant antifracture efficacy in randomized, prospective, doubleblind, placebo-controlled clinical trials before approval. All of them have been demonstrated to improve BMD measured by DXA, and most have subsequently
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Osteoporosis Prevention and Management been approved for the prevention of osteoporosis. The evidence supporting drug therapy for the prevention and treatment of postmenopausal osteoporosis (PMOP) is uniformly level 1. Teriparatide (recombinant human parathyroid hormone 1 to 34) is prescribed as a self-injected daily subcutaneous injection; calcitonin is administered as a daily nasal spray. Ibandronate can be administered as an intravenous injection once every 3 months and zoledronic acid is administered as an annual intravenous infusion. All other therapies are available as oral preparations that can be taken daily, weekly, 2 days a month, or monthly, 1 tablet per dose. Side effects are few, and there is little need to monitor for silent biochemical abnormalities. Despite the overwhelming evidence of safety, efficacy, and ease of use of osteoporosis therapies, compliance and persistence with therapy is suboptimal.25 Additionally many perhaps mostpatients who have sustained an osteoporosis-related fracture or are at increased risk of sustaining such a fracture have not been diagnosed with osteoporosis and are not prescribed therapy. This article will focus on the evidencebased guidelines that have been prepared by many professional organizations aimed at assisting the clinician in the:  Initial evaluation of postmenopausal women who should be considered for BMD evaluation by DXA  History, physical examination, and laboratory testing in those women being considered for pharmacologic intervention  Monitoring and management of women for whom therapy is prescribed.

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nization of a new paradigmFRAXfor estimating the 10-year fracture risk of an individual patient based on history, anthropometry, and BMD. Direct access to the FRAX program by healthcare professional is available at www.shef.ac.uk/ FRAX, and full details of this paradigm and the implications for future osteoporosis care have been published.611 Bone mass, BMD, and bone strength all reach their maximum during the third decade of life and, in health, remain stable until the sixth decade at which time the universal phenomenon of age-related bone loss begins and continues at a slow rate for the remainder of life. In women, bone loss accelerates at menopause with this accelerated rate lasting 5 to 7 years. Not surprisingly, PMOP is the most common form of the disease. In this review, several options for the prevention and management of osteoporosis, both before and after fracture, will be presented. At the outset it must be emphasized that the only way to determine whether osteoporosis is present before fracture is by DXA measured at the abovementioned skeletal sites. It must also be emphasized that many, perhaps most, PMOP-related fractures occur in women in whom the t score is not yet 2.5 or lower and that BMD-independent risk factors for fracture are a crucial part of the clinical evaluation for every postmenopausal woman.

Universal Prevention Strategies

During infancy, childhood, and adolescence, every effort should be made to optimize peak adult bone mass (PABM), recognizing that as much as 75% of PABM is genetically determined.12,13 Nongenetic factors that could have adverse effects on PABM that must be considered include nutrition, exercise, disease, and medication. Pregnancy and lactation place an added strain on maternal

The most up-to-date guidelines were released by the National Osteoporosis Foundation in the United States in February 2008 (www.nof.org/professionals/ Clinicians_Guide.htm). These guidelines followed quickly on the heels of the announcement by the World Health Orga-

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bone mass, and nutritional support of the skeleton must be adjusted accordingly. Exactly when during the menopause transition bone loss begins to accelerate is not yet certain, but all would agree that by 12 months after the last menstrual period, some increased bone loss is apparent. As with other clinical and laboratory manifestations of the menopause, there is considerable person-to-person variability in the rate and duration of accelerated postmenopausal bone loss. There seems to be little relationship between gonadal steroids and gonadotrophins and the extent of bone loss, but there is some evidence that biochemical markers of bone resorption may provide some information in this regard.14 Estrogen provided for menopausal management offers protection against this bone loss but only for as long as the estrogen is taken. Here too, there is considerable individual variability in the amount of estrogen required to prevent bone loss.15 All guidelines recommend a daily intake of calcium (1200 to 1500 mg daily from food and/or supplements) and vitamin D (800 to 1000 units, generally from supplements) for all postmenopausal women. These guidelines also recommend regular weight bearing and strength training exercise, but the amount recommended varies substantially and the evidence supporting any specific amount or type is minimal. Importantly it must be remembered that for most women rigorous attention to these universal guidelines alone is not sufficient to reduce the likelihood of developing PMOP later in life. The final item in this list of universal prevention strategies is fall prevention. This too must be tailored to the individual persons overall health, medication, physical fitness, gait, vision, hearing, living environment, etc. While most falls do not result in hip fracture, even in the elderly, most hip fractures are the result of a fall.

When Should Prevention Strategies Be Initiated in Relation to the Menopause Transition?

While some practitioners recommend that all women should have BMD measured during this menopausal transition, such measurement has not been accepted by any of the published evidence-based guidelines (http://www.iscd.org/Visitors/ positions/OfficialPositionsText.cfm, http:// www.nof.org/professionals/Clinicians_Guide. htmon a single bone density measurement. The United States Preventive Services Task Force recommended that BMD should be measured in all women of age 65 or older (if not already done).20 Clinical practice guidelines published by many professional societies concur with this recommendation but add further that BMD testing should be performed earlier if there are one or more BMD-independent clinical risk factors present (Table 1). This underscores the importance of obtaining the appropriate skeletally oriented history at each annual physical examination.

Pharmacologic Intervention at the Menopause

As has been noted, estrogen ( progesterone in women with an intact uterus) will prevent early postmenopausal bone loss, apparently for as long as such therapy is continued. Whether or not to prescribe hormone therapy at menopause is an individual decision to be made by the patient and her doctor, but most current recommendations, based on the data from the Womens Health Initiative study, state that such therapy should preferably not be started solely for the prevention of bone loss. If a decision is made to begin hormone therapy for nonskeletal reasons, there is little indication to measure BMD before therapy.

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TABLE 1. Risk Factors for Minimal Trauma Fractures That Should Be Considered in the Decision About Intervention to Prevent Fractures in Women With BMD t Score in the Low Bone Mass (Osteopenia) Range

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TABLE 2. Conditions That Should Be Considered When Evaluating the Possibility of a Secondary Cause for Bone Loss
Nutritional Malnutrition from any cause Low calcium intake Low vitamin D intake Excess sodium intake (promotes hypercalciuria) Excess vitamin A intake (>20,000 units/d many multivitamins contain 10,000 units/dose) Alcoholism Endocrine disorders Primary hyperparathyroidism Hyperthyroidism (mainly a concern with chronic excess exogenous thyroxine) Cushing syndrome/disease Hyperprolactinemia Type 1 diabetes (type 2 diabetes is associated with increased fracture risk at a higher BMD than nondiabetics) Gastrointestinal diseases Chirons disease Inflammatory bowel diseases Any surgical procedure resulting in shortbowel syndromes, particularly bariatric surgery Chronic liver disease Medication Glucocorticosteroids (a safe dose has not been established but 5 mg/d or more of prednisone should be cause for concern. The data on inhaled or nasal steroids is unclear) Antiepileptic medications Proton pump inhibitors Thyroxine Furosemide Thiazolidinediones (appear to increase fracture risk in type 2 diabetes even when BMD is not particularly low) Aromatase inhibitors Depomedroxyprogesterone acetate (BMD is low in women taking DMPA but appears to recover after therapy is discontinued. There is no good evidence that prior DMPA use affects postmenopausal BMD)
Many DXA reports include a t score (BMD relative to the mean value in the young normal reference population) and Z score (BMD relative to the mean value in patients matched for age, sex, and ethnicity). A Z score lower than 2.0 suggests that the BMD is lower than expected but the majority of patients with a secondary cause of bone loss do not have a Z score 2.0 or lower. This list is targeted toward postmenopausal osteoporosis and is not an exhaustive list of all secondary causes of bone loss. BMD indicates bone mineral density; DMPA, depot medroxyprogesterone acetate; DXA, dual-energy x-ray absorptiometry.

Personal history of fracture after age 45 Family history of osteoporosis with fracture Current smoker History of frequent falls
BMD indicates bone mineral density.

In women not prescribed hormone therapy for management of the menopause, if BMD is measured and the t score is 1.0 or better, no pharmacologic intervention is indicated. If the t score is 2.5 or lower, it is essential that a thorough search for secondary causes of bone loss be undertaken (Table 2). If no secondary cause is found, therapy should be initiated with one of the approved therapies for the treatment of osteoporosis (Table 3). If the t score is between 1.0 and 2.5, consideration should be given to prescribing one of the several approved therapies for the prevention of osteoporosis (Table 3). For many of these women, particularly those in whom the t score is not below 2.0, this initial BMD measurement may simply reflect PABM, and intervention may not be appropriate. As previously noted, in this group of women, there is evidence that measurement of the biochemical markers of bone remodeling (Table 4) can help identify those women in whom rapid bone loss is more likely to occur over the next 4 years, and, by inference, are most likely to benefit from pharmacologic intervention. Garnero and colleagues14 dichotomized over 4000 postmenopausal women into 2 groups those in whom the level of the marker was still within the reference interval (mean 2 SD) for premenopausal women were considered to have low bone turnover; those in whom the value was

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FDA-approved Therapies for the Prevention and Treatment of Postmenopausal Osteoporosis
Prevention Treatment + + + + + + +

TABLE 3.

Alendronate Ibandronate Risedronate Zoledronic acid Raloxifene Calcitonin Teriparatide

+ + + + +

this means that an individual practitioner must become familiar with assays most readily available to him or her and make every effort to use a single laboratory to the extent possible. The markers that are commercially available in the United States are listed in Table 4.

Pharmacologic Intervention for Postmenopausal Osteoporosis

In women who have not yet sustained a fragility fracture but who have the diagnosis of osteoporosis based solely on a low BMD (t score < 2.5), any of the FDA-approved therapies are appropriate and indicated. While the bisphosphonate class of drugs has a greater effect on BMD than either raloxifene or calcitonin, the link between the effect on BMD and the antifracture effectiveness is limited. Calcitonin is in some ways the easiest therapy to administer because it is provided as a nasal spray and has very few short-term or long-term side effects. The BMD change with calcitonin is substantially less than with other medications, but there is no evidence that compliance is improved despite the ease of use and safety. Raloxifene has an effect on BMD that is greater than calcitonin, is easy to take as a daily oral tablet but has side effects (hot flushes, increased risk of

>2 SD above the mean for healthy premenopausal women were considered to have high bone turnover. For each of the 7 markers measured, the prospectively measured 4-year decrease in BMD was <1% in those with low bone turnover and >3% for those with high bone turnover.14 Biochemical markers of bone remodeling have been used sparingly in clinical practice, and most clinical practice guidelines have made only passing reference to their use. It is only in recent years that technology for serum-based assays for these markers have replaced the earlier, less reliable urine-based assays. In particular, the issues of diurnal variation and interassay and intra-assay variability have been substantially reduced by the introduction of serum-based assays but standardization of the assays has not yet been accomplished. In practical terms,
TABLE 4.

Biochemical Markers of Bone Remodeling

NTX CTX TRAP BSAP P1NP P1CP OCN Serum* or urinew Serum* or urinew Serum Serum Serum* Serum* Serum

Resorption Amino terminal telopeptide of collagen cross-links Carboxy terminal telopeptide of collagen cross-links Tartrate-resistant acid phosphatase Formation Bone-specific alkaline phosphates Procollagen extension peptideamino terminal Procollagen extension peptidecarboxy terminal Turnover Osteocalcin
* Fasting sample required. w Timed 2-hour collection of second morning void.

Osteoporosis Prevention and Management thromboembolic disease) that may not be tolerated by some women. Against that, raloxifene has recently been approved by the FDA for prevention of breast cancer, which would clearly appeal to many women. There are also clinical trials reporting prevention against cardiovascular disease, but this is not an FDA-approved indication. The most potent antifracture therapies are the bisphosphonates that can be taken orally daily, weekly, 2 days each month, or monthly, or intravenously by injection quarterly (ibandronate) or by infusion annually (zoledronic acid). The shortterm side effects (gastrointestinal) trouble a number of women and, in an individual patient, switching to a different bisphosphonate does not always overcome this. The intravenous route would seem ideal from a compliance point of view and side effects (acute phase reaction) are uncommon and short lived. The downside is that many physician practices are not set up for either an intravenous injection or infusion. Cancer centers throughout the country are set up for this purpose and have extensive experience with intravenous bisphosphonates for treatment of skeletal metastases. Whether or not women with a benign disease, osteoporosis, feel comfortable receiving therapy in a cancer treatment center has not yet been formally studied. Patients often inquire about which bisphosphonate is best. Until recently, this has not been formally addressed but, in December 2007, the Agency for Healthcare Research and Quality issued a statement indicating that there is no evidence to support the use of one over the other (http://www.ahrq.gov/news/press/pr2007/ osteomedpr.htm). In women in whom the diagnosis of osteoporosis is established at the time of the first fragility fracture, the initial treatment of choice remains bisphosphonate as all controlled clinical trials included women with 1 or more such fractures. In

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women who sustain a fracture while on bisphosphonate therapy, consideration should be given to switching to treatment with teriparatide by daily self-administered subcutaneous injection. This therapy should also be considered for women who present with a history of multiple fragility fractures. All randomized-controlled clinical trials of osteoporosis therapies were conducted with both the placebo and active treatment arms receiving supplemental oral calcium and vitamin D. Accordingly all patients treated for osteoporosis must be prescribed these supplements. Equally important is the need to restate and emphasize fall prevention, and to stress the importance of compliance with therapy. Monitoring the response to therapy remains a big problem and a barrier to medication compliance and persistence. BMD measured by DXA is only covered by Medicare once every 2 years, and some carriers do not cover any followup densitometry studies. Patients need positive feedback earlier than that and to faithfully take medication for 2 years only to learn that BMD has not increased is disheartening. The bisphosphonates act by inhibiting bone resorption, and most clinical trails have included data indicating that biochemical markers of bone resorption (or formation) are significantly reduced from baseline within 3 months of initiating therapy. While the patient is compliant with therapy, these markers remain constant and the effect on bone remodeling may last for a year or longer after therapy is discontinued. There are limited data to suggest that feedback about the biochemical response does improve compliance/persistence. This has been addressed in some studies but the level of evidence is not strong. The effect of an anabolic agent (teriparatide) is to increase bone formation; this too can be monitored using a biochemical marker of bone formation.

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2. Kimber CM, Grimmer-Somers KA. Evaluation of current practice: compliance with osteoporosis clinical guidelines in an outpatient fracture clinic. Aust Health Rev. 2008;32:3443. PMID: 18241147. 3. Silverman SL, Gold DT, Cramer JA. Reduced fracture rates observed only in patients with proper persistence and compliance with bisphosphonate therapies. South Med J. 2007;100:12141218. PMID: 18090964. 4. Kothawala P, Badamgarav E, Ryu S, et al. Systematic review and meta-analysis of real-world adherence to drug therapy for osteoporosis. Mayo Clin Proc. 2007; 82:14931501. PMID: 18053457. 5. Rabenda V, Mertens R, Fabri V, et al. Adherence to bisphosphonates therapy and hip fracture risk in osteoporotic women. Osteoporos Int. 2007;19:811818. PMID: 17999022. 6. Kanis JA, Johnell O, Oden A, et al. Risk of hip fracture according to World Health Organization criteria for osteoporosis and osteopenia. Bone. 2000;27:585590. PMID: 11062343. 7. Kanis JA, Johnell O, Oden A, et al. Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int. 2001;12:989995. PMID: 11846333. 8. Kanis JA, Johnell O, De Laet C, et al. International variations in hip fracture probabilities: implications for risk assessment. J Bone Miner Res. 2002;17: 12371244. PMID: 12096837. 9. De Laet C, Oden A, Johnell O, et al. The impact of the use of multiple risk factors on case finding strategies: a mathematical framework. Osteoporos Int. 2005;16: 313318. PMID: 15241584. 10. Tosteson AN, Melton LJ III, DawsonHughes B, et al; National Osteoporosis Foundation Guide Committee. Costeffective osteoporosis treatment thresholds: the United States perspective. Osteoporos Int. 2008;19:437447. PMID: 18292976. 11. Dawson-Hughes B, Tosteson AN, Melton LJ III, et al.; National Osteoporosis Foundation Guide Committee. Implications of absolute fracture risk assessment for osteoporosis practice guidelines in the

The duration of therapy with teriparatide has been set by the FDA at 2 years. For the antiresorptive class of therapies, no such time constraints for the duration of therapy have been imposed by the FDA. However, this does not mean that patients need to continue therapy indefinitely. In fact, researchers have reported that discontinuation or interruption of therapy may not be harmful.21,22 The level of evidence for this is not strong, and there are no data to indicate that such intermittent therapy is actually beneficial.

Summary and Conclusions

BMD measured by DXA is at least as strong a predictor of an adverse health outcome (fragility fracture) as cholesterol or blood pressure is at predicting acute myocardial infarction or cerebrovascular accident. Therapies for patients with low BMD or osteoporosis (diagnosed by BMD and/or fragility fracture) are safe and effective and have all been approved only after antifracture effectiveness has been demonstrated in controlled clinical trials. Compliance and persistence to long-term therapy is nonetheless suboptimal. The long interval needed for BMD follow-up and the limited change in BMD over time may be contributing factors, but earlier follow-up using biochemical markers of bone remodeling does not substantially improve this. The evidences to support the use of BMD as a screening and diagnostic tool, and the safety and efficacy of the available therapies are level 1. Improving compliance and persistence is suboptimal and remains perhaps the biggest challenge still to be overcome in the management of PMOP.

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18. North American Menopause Society. Management of osteoporosis in postmenopausal women: 2006 position statement of The North American Menopause Society. Menopause. 2006;13:340367; quiz 368369. PMID: 16735931. 19. AACE Osteoporosis Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract. 2003;9:544564. No abstract available. Erratum in: Endocr Pract. 2004;10:90. PMID: 14715483. 20. U.S. Preventive Services Task Force. Postmenopausal hormone replacement therapy for primary prevention of chronic conditions: recommendations and rationale. Ann Intern Med. 2002;137: 834839. Summary for patients in: Ann Intern Med. 2002;137:I48. PMID: 12435221. 21. Brookhart MA, Avorn J, Katz JN, et al. Gaps in treatment among users of osteoporosis medications: the dynamics of noncompliance. Am J Med. 2007;120: 251256. 22. Black DM, Schwartz AV, Ensrud KE, et al; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:29272938. PMID: 17190893.