Treatments in Endocrinology

, Volume 2, Issue 5, pp 331–345 | Cite as

Prevention and Treatment of Postmenopausal Osteoporosis

  • Aparna Mahakala
  • Shalini Thoutreddy
  • Michael Kleerekoper
Review Article


Osteoporosis is a systemic disease characterized by low bone mass and microarchitectural deterioration of the skeleton leading to enhanced bone fragility and an increased risk of fracture. Prior to fracture, diagnosis is established by documenting low bone mass. In the first section of this article we review the clinical use of bone mass measurements and biochemical markers of bone remodeling in selecting patients most in need of preventive therapy at menopause. Women with high bone turnover lose bone at menopause more rapidly than those with normal bone turnover and are more likely to derive benefit from the several preventive therapies available. The second section addresses the available technologies used to diagnose osteoporosis and/or establish fragility fracture risk using noninvasive bone mass measurement and biochemical markers of bone remodeling separately or in combination. In the third section we review the several treatment options available for patients with osteoporosis, including alendronate (alendronic acid), risendronate (risedronic acid), calcitonin, teriparatide, and raloxifene, and the approaches to monitoring the therapeutic response. The final section deals with fall protection — an often forgotten aspect of management of the patient at risk for sustaining and osteoporotic fragility fracture.

The link between declining estrogen production at menopause and rapid bone loss leading to an increased incidence of fragility fractures later in life has been recognized since the days of Fuller Albright et al.[1] more than half a century ago. More recently, a series of elegant studies at the Mayo Clinic in Rochester, Minnesota, USA have documented the role of estrogen in the development and maintenance of the skeleton in both sexes.[2] Work begun more than 30 years ago[3,4] clearly documented the benefits of estrogen in preventing this bone loss. Many epidemiologic studies have subsequently documented that this prevention of bone loss with estrogen is associated with a reduced likelihood of fractures when compared with non-users of estrogen. While all this seems straightforward, the reality is that the majority of women who begin estrogen at menopause, perhaps as many as 80%, do not remain on this therapy for longer than 1 year. The incidence and prevalence of postmenopausal osteoporosis has risen over the past several decades, with little evidence that this increase is slowing down. The reasons for these increases are not clear and go beyond the increase in the number of older people worldwide. To address this important clinical problem a number of therapies have been developed as alternatives to estrogen to prevent bone loss at menopause, to stabilize bone loss once it has occurred, and to decrease the incidence of fractures that has resulted from so many women and their physicians not considering osteoporosis prevention at menopause.

1. Prevention of Bone Loss at Menopause

At menopause, the decline in estrogen production stimulates cytokines (interleukin [IL]-1 and IL-6, and tumor necrosis factor [TNF]-α) to resorb bone at an accelerated rate that is substantially greater than the capacity of osteoblast-mediated bone formation to lay down new bone.[5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15] This net negative skeletal balance is such that it has been estimated that as much as 20% of a woman’s bone mass will be lost in the first 5 years post menopause, but these estimates vary widely.[16,17] Clearly this rate of bone loss cannot be sustained for the average postmenopausal life expectancy of 30 years, but the mechanisms responsible for deceleration of this bone loss are not well understood. Bone loss in these first few years post menopause is, to a great extent, reversible, as so elegantly demonstrated almost two decades ago by the work of Aitken et al.[3] Studying a group of women from the time of surgical menopause, these researchers demonstrated that those women receiving placebo continued to lose bone throughout the 15 years of study. Those women receiving estrogen together with a progestogen (progestin) from the time of surgery experienced no bone loss as long as therapy was continued. Those women in whom therapy was not begun until 6 years postsurgery had no further bone loss but did not experience any bone gain. Women commenced on therapy just 3 years postsurgery were able to regain most, but not all, of the bone that had been lost and maintained that level of bone mass as long as therapy was continued.

In theory, any agent that inhibits bone resorption should prevent postmenopausal bone loss when begun within 3 years of menopause. However, to our knowledge this has only been shown in clinical trials with estrogen (with or without a progestogen) or bisphosphonates. Carefully conducted controlled clinical trials of calcium supplements alone did not demonstrate any skeletal protective effect when given within 5 years of menopause, except in women with habitually very low (<200 mg/day) dietary calcium intake.[18] Clinical trials with the selective estrogen receptor modulator raloxifene did include some women within 5 years of menopause. However, the median time post menopause of the 1764 women enrolled in the three clinical trials was 5 years.[19] This seemingly small difference in the timing of initiation of therapy may explain why the increase in spine bone mineral density (BMD) [compared with patients on placebo] was only about 3% with raloxifene and 5–6% with estrogen,[20, 21, 22, 23, 24] alendronate (alendronic acid),[25, 26, 27, 28] and risedronate (risedronic acid).[29,30] It should be noted that, in most of these clinical trials, all patients received supplemental calcium, thus underscoring the ineffectiveness of calcium monotherapy in preventing early postmenopausal bone loss.[31] This has also been demonstrated for vitamin D supplementation in addition to estrogen.[32,33] Another pertinent observation in these studies is that the extent of bone loss in the placebo arms of these trials was more marked in the lumbar spine than in the proximal femur, as was the increase in BMD in the active treatment arms. Thus, the lumbar spine appears to be the preferred site for BMD measurement in early post menopause.

1.1 Selecting Patients for Preventive Therapy

Although there is a great deal known about osteoporosis prevention and treatment by healthcare providers, how this information should be transferred to the patient is unresolved. A series of focus groups involving 300 women in the US indicated that providers are not meeting the needs of the patient in this regard.[34] Discussions, if undertaken at all, tend to relate to fractures and little is said about the difficulties women face in terms of mobility and the ability to regain daily functioning after a fracture has occurred. The use of BMD testing as a screening tool has been controversial, mainly because of economic concerns rather than any scientific issues. Randomized trials have assessed the impact of osteoporosis education, with and without BMD measurement, on the initiation of both diet and lifestyle changes and pharmacologic intervention in postmenopausal women not currently receiving preventive therapy for osteoporosis.[35,36] Education regarding osteoporosis prevention appears to encourage women to make lifestyle changes such as discontinuing cigarette smoking, avoiding excessive alcohol intake, increasing dietary calcium intake, and performing weight-bearing exercises. It is worth noting that these have been a major focus of many education programs despite the limited documentation of the effectiveness of these changes. The inclusion of BMD testing enhances the likelihood that women will consider pharmacological therapy.[36] Since the fracture rate is so low in the early postmenopausal years, risk factors for fracture are of little benefit in selecting patients for preventive therapy. Risk factors for low bone density have been evaluated, but the sensitivity and specificity is so poor that they are not good surrogates for a BMD measurement. In contrast, in the elderly there is good evidence that historical risk factors can be used to predict fracture risk.[37]

It is often stated that as up to 20%, on average, of bone is lost during the first 5 years post menopause, a case could be made to offer pharmacologic intervention to all women as they enter menopause. Several studies have demonstrated that there is considerable variability in the rate of bone loss in these early postmenopausal years.[38, 39, 40, 41, 42, 43, 44, 45, 46] The rate of loss appears to be related to the rate of bone remodeling as assessed by biochemical markers.[47, 48, 49] In a 4-year prospective study women were categorized as having normal (marker value within 2 SD of the premenopausal mean) or increased (marker value >2 SD above the premenopausal mean) bone turnover.[48] For each of the markers studied (figure 1) bone loss was trivial (<1% in 4 years) in those with normal turnover and significantly greater in those with increased turnover.
Fig. 1

Prospectively measured bone loss in early postmenopausal women as a function of baseline markers of bone turnover. High bone turnover is defined as values for the turnover markes which were above the reference interval for premenopausal women. Low bone turnover is defined as values for the turnover markers which were within the reference interval for premenopausal women (adapted from Garnero et al.,[48] with permission from the American Society for Bone and Mineral Research). BAP = bone alkaline phosphatase; CTX = carboxy-terminal telopeptide of collagen cross-links; NTX = amino-terminal telopeptide of collagen cross-links; P1CP = carboxy-terminal procollagen extension peptide of type 1 collagen; P1NP = amino-terminal procollagen extension peptide of type 1 collagen.

The package inserts for FDA-approved therapies for the prevention of osteoporosis (estrogen, alendronate, raloxifene, and risedronate) suggest that these should be considered in postmenopausal women in whom the T-score is −1.0 or lower. A number of organizations have published guidelines for the prevention and/or treatment of osteoporosis and none recommend therapy for all women with a T-score −1.0 or lower.[50, 51, 52] BMD in healthy premenopausal women is normally distributed around the mean value, so that 16% of all healthy women entering menopause will have BMD values below this value. Women with a family history of osteoporosis with fractures and a BMD T-score −1.0 or lower should probably be considered for therapy without further testing, as should women with a personal history of fragility fracture. In the absence of such a family or personal history it would seem appropriate to measure a biochemical marker of bone remodeling and offer therapy to those in whom the marker value is elevated. As recently pointed out, there are still practical technical issues with measurement of these markers, and their use in this context must be guided by the physician’s personal experience with the markers that are readily available to them.[53,54] The recent availability of serum-based assays for the two most widely used markers of bone resorption, the amino-terminal telopeptide of collagen cross-links (NTX)[55, 56, 57, 58] and the carboxy-terminal telopeptide of collagen-cross-links (CTX or CrossLaps),[59, 60, 61, 62, 63, 64, 65, 66, 67] appears to have minimized many of the assay problems, particularly where these assays have been placed on automated platforms.[68,69]

1.2 The Timing and Duration of Preventive Therapy

Conventional teaching has been that it is crucial to begin prevention of postmenopausal bone loss as early as possible after menopause, since bone loss is accelerated at this time but only for some 5–7 years. While there is clearly nothing wrong with this approach and there is no clear indication to delay intervention, the results recently reported from the estrogen/progestogen (HRT) arm of the Women’s Health Initiative (WHI)[70] trial should cause us to question this conventional teaching. The individuals enrolled in this study were not selected because of an increased risk of osteoporosis or fracture, and in most cases BMD was not measured. Only one-third of individuals were aged 50–59 years, with the remainder being aged 60–79 years. While data regarding time since menopause have not yet been published, it is likely from the age distributions that at least 70% of the study participants were more than 5 years post menopause. Yet 5.2 years of HRT was clearly sufficient, even in this age group, to result in significantly fewer osteoporosis-related fractures than in those receiving placebo. To recommend a paradigm shift to hold back a decade before initiating therapy to prevent postmenopausal bone loss would be foolhardy on the basis of just one, albeit excellent, clinical trial. Nonetheless, it is an important observation with a potentially major impact on healthcare costs to both the individual and society.

The decision about pharmacologic therapy to prevent early postmenopausal bone loss should be reviewed annually by the physician and patient. If the initial decision is to withhold therapy, provided there is no change in personal medical history or family history of osteoporosis, BMD should be repeated after an interval of 2 to 3 years. It is likely, but surprisingly not yet proven, that bone lost during a 2- to 3-year interval is reversible bone loss. Longer intervals between serial BMD measurements in untreated early postmenopausal women may result in greater irreversible bone loss. Any statistically significant decrease in BMD should be a trigger for offering pharmacologic intervention.

It is crucial that clinicians understand what change in BMD actually represents bone loss. As with any measurement, in medicine and elsewhere, there is some imprecision with repeat measurements. Even under the most rigorous research circumstances there is about 0.5% method imprecision when measurements are made in the lumbar spine in early postmenopausal women. At the hip the precision error in the best circumstances is 1%. In routine clinical practice method imprecision is much greater than this, and may be as high as 2.5% for the spine and 5% for the hip. The largest contributor to precision with BMD measurements is the experience of the operator. A technician working full-time on BMD measurements is likely to obtain more reproducible results than a medical office assistant performing just two or three measurements a week. Similarly, in busy radiology suites with a number of technicians assigned to BMD on a rotation basis the precision will not be as good as if one technician performed all the measurements. Any program performing BMD measurement as a clinical service should perform appropriate studies to determine the (skeletal site) precision in their program. Once that is known it is possible to determine, with 95% confidence, whether two serial measurements are statistically significantly different from each other or whether differences might be accounted for simply by method imprecision. Another major contributing factor to misleading information from serial BMD measurements occurs when measurements are not performed on the same instrument. The reason so much emphasis is placed on method precision (or imprecision) is that the expected change in BMD in many circumstances is so close to these limits. Some caveats should be noted:

  • the onus is on the person reporting BMD results to determine the method imprecision in his/her program and comment in the BMD report whether any change is or is not statistically significant;

  • in clinical practice it may not be necessary to know about change in BMD with 95% confidence — 75% or 80% may be sufficient and there are statistical formulae for the reporting program to determine these confidence intervals;

  • knowledge of method imprecision and confidence about whether or not a change in BMD is significant applies equally when one is anticipating an increase in BMD.

If the initial decision is to begin pharmacologic therapy, treatment (if tolerated) should be continued for at least 2 years before repeating BMD. It has been suggested that pretreatment and/or early (3-month) measurement of a biochemical marker of bone remodeling is a useful adjunct to provide positive feedback to the patient that the therapy is effective; however, the effectiveness of this tactic has not been formally documented.

A significant decrease in BMD after 2 years of therapy should be cause for concern and, after confirming that the patient has been compliant with therapy, a search for secondary causes of bone loss should be initiated. At the same time, it must be emphasized that lack of a significant increase in BMD following 2 years of therapy does not indicate treatment failure. The goal of therapy in this population is to prevent bone loss, not to increase BMD. Any increase in BMD on therapy in the early (within 5 years) postmenopausal period will only be a replacement of bone that had been ‘lost’ between menopause and initiation of therapy. The increase in bone remodeling that typifies early postmenopausal bone loss results in a transient loss of bone known as the remodeling space. After a while, this bone loss is no longer transient but seemingly irreversible. Increases in BMD during the early phases of antiresorptive therapy are generally larger than in subsequent years.

This reflects closure of the transient remodeling space. In addition to raising questions about the timing of preventive therapy, the WHI report,[70] as well as several other important publications,[71,72] raises issues about the duration of therapy. Once initiated for a clear indication, preventive therapy should probably be continued lifelong, but it is not likely that the majority of women would comply with this. It has been demonstrated that the BMD benefits of estrogen persist only as long as the drug is taken. With bisphosphonates it appears that BMD benefit may persist for as long as a year after therapy has discontinued. For none of these therapies is there any prospective data on fracture protection once therapy has been discontinued and it is unlikely that any such data will be forthcoming. No doubt the women in the recently terminated WHI trial[70] will continue to be observed for many more years in order to document long-term benefit or harm after discontinuing HRT. The limiting factor in obtaining useful prospective antifracture data after discontinuation of HRT will be whether the trial participants subsequently start on other bone protective therapy.

1.3 Selecting Preventive Therapy for Patients

Estrogen is most often prescribed not for the prevention of osteoporosis but for the management of early postmenopausal symptoms. It would seem reasonable, without either BMD or biochemical testing, to continue women on estrogen prescribed for this reason. At the same time it should be pointed out that knowledge of BMD not only influences a woman’s decision to begin postmenopausal hormone replacement but also increases the likelihood of remaining on therapy.[35] Epidemiologic data suggests that women should be maintained on therapy for 5–10 years to minimize the future risk of osteoporosis.[73, 74, 75] It has been demonstrated in a controlled clinical trial that such early intervention with estrogen significantly decreases the incidence of distal forearm (Colles’) fractures,[76] and two meta-analyses of controlled clinical trials have concluded that, in women aged 60 years or younger, estrogen significantly reduces the incidence of both vertebral[77] and nonvertebral[78] fractures.

As already noted, the WHI program recently decided to close the estrogen plus progestogen arm of their clinical trial after only 5.2 years of observation, almost 3 years in advance of the proposed stopping date.[70] This decision was based on more adverse outcomes (invasive breast cancer, cardiovascular and cerebrovascular disease, venous thromboembolic [VTE] events) than documented health benefits (fracture prevention, colon cancer prevention). However, this controlled clinical trial clearly documented the effectiveness of estrogen plus progestogen therapy in reducing the likelihood of osteoporotic fracture, confirming the large amount of available epidemiologic data.[73, 74, 75] The breast cancer[79, 80, 81, 82] and VTE[83, 84, 85, 86, 87] data also confirmed what had been known from observational studies and clinical trials. The increase in vascular disease was consistent with earlier data from controlled clinical trials of secondary prevention of coronary heart disease (CHD)[88, 89, 90] but at variance with the observational data suggesting cardioprotection from estrogen.[91,92] The total number of excess adverse events (over benefits) compared with placebo was low, only 19 per 10 000 women-years of therapy. The WHI investigators reported their data as reflecting a primary prevention study, apparently of sufficient importance to negate observational data concerning estrogen and the heart. However, there is controversy as to whether the WHI was a primary or secondary prevention trial,[93] given that only one-third of the enrolled individuals were aged 50–59 years, with the remaining two-thirds being 60–79 years. Furthermore, only 16–17% of the women enrolled in this clinical trial were within 5 years of menopause.[94]

Given that the majority of women are prescribed estrogen (plus a progestogen if the uterus is intact) for treatment of clinical manifestations of early menopause and that there is no available alternative therapy as effective as estrogen for this purpose, current prescribing practices should not change at early menopause. The occurrence of invasive breast cancer appeared to increase with time in the WHI, while the occurrence of CHD and VTE appeared to decrease over time.[70] The fracture prevention rate increased with time in the study. This would suggest that women who are prescribed estrogen plus progestogen for management of early menopause and who do not experience CHD or VTE early in the course of therapy are likely to derive more benefit than harm by continuing therapy.

There are no apparent nonskeletal benefits of the two bisphosphonates approved for use in postmenopausal osteoporosis, and they should probably not be prescribed without prior BMD testing. These drugs have no known long-term adverse effects and the reported gastrointestinal adverse effects, usually demonstrated early in the course of therapy, are alleviated when therapy is discontinued.[95, 96, 97, 98, 99, 100] The recommended dose of alendronate for prevention of osteoporosis (which would include preventing early postmenopausal bone loss) is 5 mg/day orally or 35mg orally once weekly. This dose does not increase BMD as much as can be achieved with the dose recommended for treatment of osteoporosis (10 mg/day, 70mg once weekly). Since there is no difference in either the incidence or severity of adverse effects, or the cost of the lower (preventive) dose, there seems limited value in prescribing this lower dose. The recommended dose of risedronate for prevention and for treatment is the same, 5 mg/day orally. A 35mg oral once a week formulation has become available in the past year.

The use of raloxifene for prevention of early postmenopausal bone loss lies somewhere between the use of estrogen and bisphosphonates. The skeletal effectiveness of raloxifene is well established. The major adverse effect, relative to estrogen, is the potential to initiate or aggravate hot flushes.[101, 102, 103] As with the gastrointestinal adverse effects of bisphosphonates, this is apparent early in the course of therapy and is rapidly alleviated when therapy is discontinued. The effect of estrogen on the occurrence of VTE is mimicked by raloxifene.[104] Again, relative to estrogen, raloxifene offers the decided advantage of having no appreciable effect on the uterus,[19,105] and is not associated with vaginal bleeding that is so often the cause of discontinuation of estrogen therapy. The early results of clinical trials with raloxifene in women not at increased risk for breast cancer highlight the potential of this drug to minimize the risk of estrogen receptor-positive breast cancer.[106,107] Thus, it is a very viable alternative to estrogen or bisphosphonates in women without early postmenopausal symptoms. As with bisphosphonates, raloxifene should not be prescribed without prior BMD testing, and prescribing should be based on the BMD, family and personal history, and biochemical assessment of bone remodeling. The recommended dosage is 60 mg/day orally.

2. Establishing the Diagnosis of Osteoporosis and Assessing Fracture Risk

The World Health Organization (WHO) has defined osteoporosis as a BMD value that is >2.5 SD below the mean young adult peak value (T-score −2.5 or lower).[108] While this definition was apparently recommended initially for epidemiologic rather than diagnostic purposes, by common usage it has become the accepted definition for diagnosis as well. The pathophysiologic definition of osteoporosis is a decrease in bone mass with microarchitectural deterioration of the skeleton leading to enhanced bone fragility and a subsequent increase in fracture risk. While not specifically included in either of these definitions, postmenopausal women who sustain a fragility fracture (fracture resulting from a trauma less than or equal to that associated with a fall from a standing height), in whom no other metabolic bone disease is identified and in whom BMD T-score is not −2.5 or lower, should also be diagnosed as having osteoporosis. The common thread in these three definitions is the increased risk of fragility fracture. There is good evidence from controlled clinical trials that women who have already sustained one or more fractures are at increased risk of subsequent fracture than women who may have the same low BMD but who have not yet sustained any fragility fractures.[109, 110, 111, 112, 113, 114, 115, 116, 117] This would suggest the primacy of microarchitectural deterioration of the skeleton over a low BMD in the pathogenesis of these fractures.

At present, there is no reliable noninvasive method of detecting microarchitectural deterioration prior to fracture, although there is encouraging preliminary data from studies with ultrasonography[118, 119, 120] and magnetic resonance imaging.[121, 122, 123, 124] While not yet fully accepted, there is very good evidence that the rate of bone turnover or remodeling, either assessed histologically[125, 126, 127, 128, 129] or biochemically,[130, 131, 132] is a reliable predictor of fracture risk independent of BMD. At least one study[130] has shown that in a population of older women the risk prediction from BMD and bone turnover markers is independent and additive (figure 2).
Fig. 2

Odds ratio for hip fracture in elderly postmenopausal women as a function of 1 SD increase in urinary carboxy-terminal telopeptide of collagen cross-links (CTX) or deoxypyridinoline (DPD) as markers of bone resorption and 1 SD decrease in hip bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DEXA). High bone resorption is defined as CTX and DPD above the upper limit of the premenopausal range. Low BMD is defined as a BMD T-score of ≤−2.5 (adapted from Garnero et al.,[130] with permission from the American Society for Bone and Mineral Research).

The relationship between BMD and fracture risk is well established, with fracture risk approximately doubling for each SD decrease in BMD.[133, 134, 135] Early studies demonstrating this relationship were all performed using methods to assess the peripheral skeleton (metacarpal-cortical index, forearm BMD measured by single photon x-ray absorptiometry). With the development of dual photon absorptiometry, these observations were confirmed at central skeletal sites (lumbar spine, proximal femur). Finally, the development of dual-energy x-ray absorptiometry (DEXA) further confirmed this relationship at both peripheral and central skeletal sites. For a number of years full attention has been focused on the use of DEXA as the ‘gold standard’ for BMD measurement, and the diagnosis of osteoporosis using peripheral measurements fell in to disrepute. Quantitative ultrasonometry (QUS), a technique that involves no exposure to ionizing radiation and heralded the introduction of smaller, less costly, and portable instruments, rekindled interest in peripheral densitometry. There are now smaller x-ray-based technologies available, capable of measuring BMD at peripheral sites (finger, wrist, and heel). With QUS the measurements are speed of sound, broadband ultrasound attenuation, and stiffness index, and decreases in any or all of these has been demonstrated to reliably reflect fracture risk.[136,137] Likewise, the relationship between decreasing BMD and fracture risk has been re-confirmed with the newer, smaller peripheral densitometers.[138, 139, 140]

The availability of central DEXA, peripheral DEXA, and QUS, all reliable predictors of fracture risk, has created considerable confusion and unease in establishing a diagnosis of osteoporosis based on a T-score −2.5 or lower. BMD is not uniform across all skeletal sites because of site-to-site differences in the absolute amount of bone and the relative amounts of cortical or cancellous bone. Furthermore, while in young healthy populations BMD is normally distributed around the mean value, the variance about that mean (as a percentage of the mean value) is quite disparate from site to site. As a percentage of the mean value, 1 SD at the radial mid-shaft is approximately 6%, while at the femoral neck it is approximately 13%. The practical implication of these differences is that at the different skeletal sites a T-score of −2.5 will impart different relative and absolute fracture risks. Many women in whom T-score is −2.5 or lower at the proximal femur would have a higher peripheral T-score and not ‘qualify’ for a diagnosis of osteoporosis if only the peripheral site was measured. Discrepancies can also occur in the opposite direction, e.g. T-score below −2.5 at the forearm and above −2.5 at the hip. This BMD discordance has led some authorities to introduce the terms ‘false-positive’ and ‘false-negative’. While correct statements with respect to establishing a diagnosis of osteoporosis based on the WHO definition, these statements are unhelpful when BMD measurement is used for its real purpose — the assessment of fracture risk in an individual patient (figure 3, Faulkner et al.[141]). In the US this problem is compounded by the many health insurance programs that will only agree to reimburse for a clinical BMD measurement if a ‘numerical’ diagnosis of osteoporosis is established by the BMD measurement.
Fig. 3

Cross-sectional age-related changes in bone mineral density (BMD) in healthy women measured by different techniques. The diagnostic threshold of a T-score of −2.5 is crossed at different ages with the different methods. However, fracture risk is not related to this threshold. For example, a woman aged 60 years in this model would only be diagnosed as having osteoporosis if BMD were measured by quantitative computed tomography. Yet any individual woman can only have a single estimate for fracture risk. Thus with a heel QUS T-score of −0.9 she would have the same fracture risk as a QCT T-score of −2.5 or a total hip T-score of −1.0 or a PA spine T-score of −1.5 (reproduced from Faulkner et al.,[141] with permission). DEXA = dual-energy x-ray absorptiometry; Lat DXA = lumbar spine BMD measured by DEXA in the lateral projection; PA = postero-anterior projection; QCT = quantitative computed tomography; QUS = quantitative ultrasound.

For practical purposes, if an individual postmenopausal woman sustains a fragility fracture she has osteoporosis no matter what the BMD. If an individual postmenopausal woman has a BMD T-score lower than −2.5 at any measured site, she too has osteoporosis. One cannot exclude a diagnosis of osteoporosis in any individual postmenopausal woman unless and until BMD has been measured at all available sites using all available technologies, and T-score is not lower than −2.5 at any site. This is clearly an impractical approach. Several organizations interested in osteoporosis have been working for some time now trying to resolve this important issue, with little progress being made. It is our opinion (and only opinion) that the most appropriate solution is to relate BMD or QUS measurement to fracture risk (quantitatively, not qualitatively) and to redefine osteoporosis in terms of a fracture risk threshold, not a BMD threshold. Certainly, clinicians should be basing intervention decisions on fracture risk and not just BMD.

In this regard, based on a review of the epidemiologic literature, the National Osteoporosis Foundation has identified four BMD-independent risk factors for osteoporotic fracture: family history of osteoporosis with fracture, personal history of fracture as an adult, current cigarette smoking, and weight <57kg.[50] There are many other putative risk factors for osteoporotic fracture, but these are not BMD-independent.

3. Treatment Options for Postmenopausal Osteoporosis

In the US the FDA has approved oral alendronate 10 mg/day or 70mg once weekly, oral risedronate 5 mg/day or 35mg once weekly, calcitonin nasal spray 200U once daily, oral raloxifene 60 mg/day, and teriparatide 20μg injected subcutaneously once daily. Each of these drugs has been approved on the basis of documented antifracture effectiveness in controlled clinical trials.[110,111,142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155] The primary fracture outcome variable in most of these trials was vertebral fracture documented by change in morphometric measurements of the spine on radiographs obtained at predetermined intervals. These intervals varied from one study to the next and this has led to a number of publications indicating that one therapy can reduce fracture occurrence earlier than another. Since these ‘morphometric’ vertebral fractures would not be detected in routine clinical practice (fewer than one-third of these are associated with acute symptoms), the significance of this chase to be the quickest to reduce fractures is obscure. The clinical trials also reported on the effects of therapy, relative to placebo, on clinically apparent vertebral fractures, non-spine fragility fractures, and hip fractures, although hip fracture was a primary endpoint only in one of the trials with risedronate.[154]

In each of the reported clinical trials all study participants received oral calcium, at least 500 mg/day, in addition to the study medication. Thus, when prescribing one of the above therapies for the treatment of osteoporosis it is appropriate to also prescribe at least 500mg oral calcium. All patients in these clinical trials were also vitamin D ‘sufficient’, a difficult term to define, but in general patients should also take a multivitamin containing 400IU of vitamin D each day. The bisphosphonates alendronate and risedronate are poorly absorbed when taken orally and must be taken first thing in the morning after an overnight fast, and with 8oz of water. No other food or drink should be taken for the 30 minutes after the tablet is ingested, including the calcium supplement. Patients are also advised to avoid being recumbent during this 30-minute period. After 30 minutes has elapsed it is advisable to eat breakfast. There are no similar restrictions for the use of raloxifene, with respect to the time of day tablets can be taken or whether they can be taken with or without meals. Calcitonin is administered intranasally, and it can be taken at any time during the day.

Head-to-head studies have shown that alendronate increases spine BMD more than either calcitonin or raloxifene.[156,157] A head-to-head study of conjugated estrogen and alendronate 10mg showed that they had very similar effects on spine BMD.[158] Conjugated estrogen had a greater effect on BMD than raloxifene when compared directly.[159] In none of these direct comparison studies was fracture an outcome variable. For reasons that are not immediately clear, estrogen appears to have a greater effect on cortical bone BMD in the radius than do bisphosphonates.[160] This does not seem to translate into any differential effect on fracture outcomes. Studies with combination therapy have demonstrated that alendronate or risedronate added to ongoing estrogen therapy resulted in slightly, but statistically significant, greater increments in BMD than either drug used alone.[161, 162, 163, 164, 165, 166] Finally, it should be documented that alendronate and risendronate are equally effective when given in daily or once-weekly doses.[167, 168, 169] In all of these comparator studies BMD, not fracture, was the primary outcome variable.

Teriparatide, a synthetic preparation of the amino 1–34 fragment of human parathyroid hormone, has recently been approved for the treatment of osteoporosis in the US. Teriparatide is an important breakthrough in therapy for osteoporosis, as it is the first agent that acts by direct stimulation of bone formation rather than inhibition of bone resorption. This is reflected in clinical trials in larger increases in BMD with teriparatide than with antiresorptive therapies. Antifracture effectiveness was demonstrated in trials of just 20 months’ duration.[170,171] However, because of the expense and route of administration, teriparatide is likely to be used mainly in patients with severe osteoporosis. Severe osteoporosis is not well defined, but might include those who have sustained multiple fractures (on or off current therapy), those with very low BMD without demonstrable cause, or those not responsive (in terms of BMD) to other therapies. It is still too early to tell just where teriparatide will find most use.

One scenario we favor, without objective support for our opinion, is that teriparatide would be appropriate first-line therapy for patients with osteoporosis (with or without fracture) in whom baseline biochemical markers of bone remodeling are at the lower end of the normal reference interval. Our rationale is that antiresorptive therapy would be less effective when resorption rates are low. This has not been demonstrated in clinical trials with antiresorptive therapy but the question has not really been directly asked in these trials. There was certainly no difference in fracture rates in patients treated with teriparatide versus antiresorptive therapy, based on pretreatment biochemical marker values.

There is an apparent fascination in the literature with combination bone formation-stimulation/antiresorptive therapy, and a number of such clinical trials are in progress. The number of combinations and permutations possible for such an approach probably exceeds the trials budget of the pharmaceutical industry and funding agencies. However, individual clinicians will have ample scope to try many combinations.

3.1 Monitoring the Therapeutic Response

The goal of treatment of osteoporosis is to prevent the first fracture from ever occurring or to prevent recurrence of fracture in those patients who have already sustained one or more fractures. All of the approved therapies have documented antifracture effectiveness. However, fracture cannot be an endpoint of individual patient care. If a fracture does not occur one cannot conclude that the drug has been effective. Likewise, if a fracture does occur on therapy one should not conclude that the drug has not been effective.

There are two, not mutually exclusive, tools for monitoring response to antiresorptive therapy: BMD and biochemical markers of bone remodeling. There are advantages and disadvantages to both and a case can be made for using both modalities to monitor the response to therapy.

Under most circumstances BMD should be monitored no more frequently than every 2 years. There are two reasons for this. First, on average in the clinical trials, a significant change in BMD in individual patients did not occur inside 2 years.[115,151,172] Secondly, most medical insurance programs do not reimburse for BMD testing performed more frequently.[173] For many patients this is a long time to wait before learning that their therapy is effective and they may request that earlier measurements be performed. This is appropriate provided the patient is informed that they may have to bear the cost of the measurements and that if the result shows no change in BMD this does not mean that the therapy is ineffective. This latter point is particularly important, even when BMD is measured at 2-yearly intervals. While antiresorptive therapy prevents bone loss in more than 90% of treated patients, in some trials as many as 40–50% of individual patients did not have a significant increase in BMD but simply preservation of BMD. There is only limited data linking change in BMD to a decrease in fracture rate.[174, 175, 176]

Serial measurements of BMD should, as far as is practicable, be performed on the same instrument and serial results directly compared with the baseline data, not only with respect to derived data such as T-score, but also the primary data such as the area of bone measured and the measured bone mineral content. The only time one should have concern about treatment failure as a result of a follow-up BMD measurement is if the follow-up value is significantly lower than the baseline value. The technical quality of the serial scans must be verified before regarding the bone loss as an indication of treatment failure. The currently approved drugs are so effective at preventing bone loss that any significant bone loss should trigger a search for a secondary cause of bone loss that has supervened since therapy was started.

With the exception of teriparatide, the available drugs for osteoporosis all work by inhibiting bone resorption. The effectiveness of therapy can therefore be monitored by documenting that resorption is indeed being inhibited. Biochemical markers of bone resorption can be shown to decrease significantly within 3–4 weeks of therapy,[177, 178, 179, 180, 181, 182, 183] reaching a nadir by about 3–4 months and remaining low as long as therapy is continued. The markers of bone formation also decrease with antiresorptive therapy but this is not generally seen until 3–4 months after therapy has started, reaching a nadir at 6–9 months and also remaining low as long as therapy is continued. These changes have been well documented in controlled clinical trials, and a recent report demonstrated that these changes are associated with fracture risk reduction[183] (figure 4).
Fig. 4

Risk of new vertebral fractures with change in serum osteocalcin and in serum bone-specific alkaline phosphatase after treatment with raloxifene vs placebo. P-values are for differences between the 1st and 3rd tertiles (reproduced from Bjarnason et al.,[183] with permission). RR = relative risk.

Unfortunately, in clinical practice the effectiveness of using these markers to monitor the response to therapy has not been so straightforward. In part this is because of the biologic variability of the markers and the attention to detail required for specimen collection, particularly the urine markers of resorption. There is also some variability in the reagents used to measure these markers, such that even attention to specimen collection does not sufficiently minimize the variability. This is less of a problem for the serum-based markers of bone formation, but is still not completely eliminated. While not available as yet in the US, studies with serum CTX, particularly when performed on automated platforms, indicate that diurnal variation is less of a problem with this marker and, overall, variability is reduced.

Since teriparatide is a bone formation-stimulation agent, effectiveness can be more readily monitored by serial measurement of BMD. With this drug, failure to increase BMD should probably be regarded as a failure of therapy although, to our knowledge, there are no data linking the extent of increase in BMD to the effectiveness of fracture prevention.

4. Fall Protection

BMD is the single most important determinant of fragility fracture, and this article focuses on this aspect of the prevention and treatment of postmenopausal osteoporosis. There are also BMD-independent risk factors for fracture, of which the most important is fall protection. Muscle strength decreases with aging, as does balance and vision. Each of these factors contributes to risk of falling and sustaining a fragility fracture. Every effort should be made to ensure a safe environment both inside and outside the home for the elderly. Adequate lighting, corrective lenses for impaired vision, nonslip floors and rugs, and placement of telephone and electrical cords such that they do not pose a hazard are important aspects of fall prevention which minimize risk of falling. Using walking aids when outside in icy, windy, or snowy conditions, is equally important. For those known to be at increased risk of falling because of neurologic abnormalities, hip-protector pads have been demonstrated to be very effective in limiting the risk of hip fracture.[184, 185, 186, 187, 188] Such devices are commercially available but in controlled trials compliance with their use has been suboptimal.[184] ‘Iatrogenic’ falls are unfortunately not uncommon. Medications that cause postural hypotension or drowsiness or sedation have been associated with an increased fracture risk. When these medications cannot be avoided the patient and caregivers should be provided with counseling on fall protection.

There are a number of patients who, when told they have low BMD or osteoporosis, become so fearful of fracture after falling that they limit their activities. For such individuals, it is imperative to put the BMD measurement into perspective and remind them that regular exercise helps maintain muscle strength and agility as well as balance, and is in that way far more beneficial in fracture protection than avoiding physical activity.

Vitamin D insufficiency is an increasingly recognized problem in the elderly, a problem aggravated in winter months where ultraviolet exposure is severely curtailed. Not only is vitamin D insufficiency detrimental to the skeleton, but it is also associated with proximal muscle weakness and an increased risk of falling and fracture. A simple preventive measure is to provide all persons over the age of 70 years with 400–800IU of vitamin D daily.

5. Summary

All women who become menopausal are at risk for rapid bone loss which, if left untreated, may lead to the development of osteoporosis and an increased risk of fragility fractures. Effective therapies exist to prevent early postmenopausal bone loss. If this critical period for intervening is missed, there are fortunately very effective therapies for treating osteoporosis and reducing fracture risk after the disease has developed. The diagnosis of osteoporosis can be made prior to the development of fracture by measurement of BMD. Diagnosis cannot be made by measurement of biochemical markers of bone remodeling, although these markers can be used alone or in combination with BMD to predict fracture risk. Once therapy is initiated, biochemical markers of bone remodeling or BMD can monitor the response.


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Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  • Aparna Mahakala
    • 1
  • Shalini Thoutreddy
    • 1
  • Michael Kleerekoper
    • 1
  1. 1.Division of Endocrinology and MetabolismWayne State UniversityDetroitUSA
  2. 2.Endocrine DivisionDetroitUSA

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