INTRODUCTION

Awareness of osteoporosis has increased in recent years, but this condition remains underdiagnosed and undertreated. Patients often do not adhere to prescribed treatment regimens, resulting in poor treatment outcomes and increased risk of fractures. Fractures as a result of osteoporosis have serious negative consequences for the patient and for society as a whole, including increased morbidity and mortality, increased disability and activity limitations, chronic pain, and increased medical costs.

A range of treatment options is available for osteoporosis, and new treatments are emerging. Current therapeutic options may be classified according to their effect on bone remodeling. Those that reduce bone turnover (antiresorptive or anticatabolic drugs) include the bisphosphonates alendronate, risedronate, and ibandronate; the selective estrogen-receptor modulator (SERM) raloxifene, and salmon calcitonin. Drugs that increase bone turnover are called anabolic, or bone-forming, of which only one (teriparatide) is currently approved. The various pharmacologic agents vary in their dosing frequency and administration, and in their efficacy and tolerability profiles. Nonpharmacological approaches to the management of osteoporosis include regular physical activity, adequate intake of calcium and vitamin D, and avoidance of cigarette smoking, excess alcohol, and drugs known to be harmful to bone. Finally, for patients with poor balance and a high risk of falling, interventions to reduce fall risk or provide protection from the effects of falling may be helpful.

Newer treatment options for osteoporosis focus on nonparenteral routes of administration to avoid the gastrointestinal side effects and poor absorption of oral agents and to improve adherence with less frequent dosing. Intravenous bisphosphonates include ibandronate (approved for injections every 3 months) and zoledronic acid (ZA) [not approved for the treatment of osteoporosis at the time of this writing]. The biologic agent denosumab, given as subcutaneous (SC) injection every 6 months, is in phase 3 clinical trials. This monograph will review recent data for current and emerging options in the treatment of osteoporosis.

CHALLENGES IN OPTIMAL OSTEOPOROSIS CARE: ARE WE SCREENING AND TREATING APPROPRIATELY?

E. Michael Lewiecki, MD

In recent years, there has been substantial progress with regard to the detection and treatment of osteoporosis. There is increasing awareness of osteoporosis among the general public and among healthcare providers. Diagnosis has been simplified due to the wide availability of bone density testing with dual-energy x-ray absorptiometry (DXA), using clinical tools such as the World Health Organization (WHO) classification of bone mineral density (BMD).1 Safe and effective therapies are available. Many targeted agents are now in development thanks to recent advances in the understanding of bone physiology. 

However, there is still considerable room for improvement in the management of osteoporosis. Osteoporosis remains underdiagnosed and undertreated, and calcium and vitamin D deficiencies are common.2  There is concern that recent changes to Medicare reimbursement for DXA may restrict the availability of BMD testing, further reducing the rates of diagnosis. Adherence to treatment regimens is poor,3,4 limiting effectiveness of therapy and contributing to poor clinical outcomes, higher rates of fracture and the consequences of fracture, and higher costs of medical care. This discussion will explore some of the challenges to optimal osteoporosis care and explore potential solutions.

Diagnosis of Osteoporosis and Appropriate Treatment Decisions

The WHO classification of BMD is widely used in the diagnosis of osteoporosis.^1,5,6  This method classifies BMD into 4 categories—normal, osteopenia, osteoporosis, and severe osteoporosis—by comparing the patient’s BMD to that of a young-adult reference population expressed as a T-score.⁵  The lower the T-score, the greater the risk of fracture. For every 1 standard deviation that BMD decreases, there is approximately a doubling of fracture risk.^7,8  The WHO classification system allows physicians to identify patients in high-risk categories before a fracture occurs and has helped to increase awareness of osteoporosis among the general public.⁵

However, there are limitations to the applicability of the WHO classification. The WHO
T-score criteria apply only to the BMD measured by DXA at the hip, lumbar spine, and forearm, and cannot be used with other measurement techniques or at other skeletal sites.^5,6  Furthermore, the WHO classification was based on a population of postmenopausal Caucasian women; it is not clear if or how the classifications can be extrapolated to non-Caucasians, younger women, or to men.⁵ Finally, there is no generally accepted standard reference population for calculating T-scores. All of these factors can lead to variations in T-score and their interpretation, which can result in differing estimates of fracture risk and osteoporosis prevalence.^5,6

A key element in the management of osteoporosis is recognition that T-score alone does not provide a complete assessment of fracture risk. A wide variety of clinical factors have been identified that independently affect the risk of fracture. In a prospective study in 9516 Caucasian women aged 65 years or older with no history of hip fracture, a variety of risk factors were evaluated for their influence on the frequency of hip fracture over 4.1 years (listed in Table 1).⁹ Many of these risk factors independently influenced the risk of hip fracture, and the greater the number of risk factors, the greater the risk of fracture (Figure 1).⁹ Among women with 2 or fewer risk factors, the incidence of fracture was 1.1 per 1000 woman-years (95% confidence interval [CI], 0.5-1.6).  In comparison, among women with 5 or more risk factors (including older age and prior fracture but not low BMD), the incidence of fracture was 19 per 1000 woman-years (95% CI, 15-22), and this was increased to 27 per 1000 woman-years (95% CI, 20-34) in patients with 5 or more risk factors and BMD in the lowest third for their age.⁹ To provide the best estimate of fracture risk and identify those patients most likely to benefit from therapy, the T-score should be combined with clinical risk factors for fracture.¹⁰

Most clinical practice guidelines now use a combination of T-score and various risk factors to recommend which patients should be treated. However, the guidelines vary according to the population that is addressed, which risk factors are used, and what T-score cut-offs are used.⁵ Treatment choices should reflect the risk factors associated with the individual patient: for example, a patient with an increased risk of hip fracture that is primarily due to low BMD may be more likely to benefit from pharmacologic intervention than a patient whose fracture risk is high due to poor vision, imbalance, or a high risk of falling.

The WHO and the National Osteoporosis Foundation (NOF) have used fracture risk assessment with cost-utility analyses to calculate intervention thresholds.⁵  An intervention threshold is generally expressed as the 10-year probability of fracture at which pharmacological therapy becomes cost effective using numerous country-specific medical, economic, and social assumptions.^11,12  Borgström et al estimated intervention thresholds for 7 countries, including the United States, using as many country-specific data as possible for each.¹¹  Figure 2 shows the results for the United States. The intervention thresholds, ¹¹ here expressed as the 10-year hip fracture probability at which it becomes cost effective to treat, are shown along with the fracture risk in the general population for each age group. This illustrates the rise in fracture risk with advancing age, and shows that in the older age groups it is cost effective to treat those with a below-average fracture risk. The final decision to treat and how to treat should consider factors in addition to cost effectiveness, such as patient preferences, comorbidities, and affordability.

Unmet Needs in the Management of Osteoporosis

Despite ongoing educational campaigns to increase screening for osteoporosis, this condition remains underdiagnosed and undertreated. In a retrospective study using data from the National Health and Nutrition Examination Survey (NHANES) III and IV, patient reported awareness of a diagnosis of osteoporosis was compared with prevalence of osteoporosis determined by DXA-measured femoral BMD in women aged 50 years and older.¹³ Among women in the study, a diagnosis of osteoporosis was lower than BMD-determined prevalence starting at 60 years of age, with this discrepancy increasing with advancing age (Figure 3).¹³ The study suggests that half of all elderly women (≥80 years of age) with osteoporosis in the United States are not being diagnosed.¹³  Other studies have shown that the “treatment gap,” the difference between those who would benefit from therapy and those who actually receive it, is even greater. In 2003, the Health Plan Employer Data and Information Set (HEDIS) showed that among women aged 67 years or older who had experienced a fracture, only 18% were being treated for osteoporosis or had received a DXA test.¹⁴

The foundation of any program to optimize skeletal health and the response to therapy includes an adequate intake of calcium and vitamin D.¹⁵  Unfortunately, calcium and vitamin D deficiencies are common, even in women being treated for osteoporosis. In a recent study, more than half (52%) of postmenopausal women in North America receiving treatment for osteoporosis had serum levels of 25-hydroxyvitamin D <30 ng/mL, the target value identified by many experts.¹⁶  A high prevalence of vitamin D inadequacy was seen in all age groups and at all latitudes.²

Adherence

Among women who receive treatment for osteoporosis, adherence to the treatment regimen is often less than optimal, which can adversely affect clinical outcomes. The origin of poor adherence is multifactorial, and includes cost of the medication; side effects, whether actual or feared; poor understanding of the potential consequences of osteoporosis; or belief that such consequences are an inevitable result of aging.^3,4  In one study of 11,249 women with osteoporosis, just under half were "highly compliant" (defined as having drug in the patient’s possession for at least 80% of the time for which it was prescribed) over the entire period of follow-up (1996 to 2001).¹⁷ Patients who were highly compliant had a significantly lower annual fracture rate compared with patients who did not comply with treatment (by 25.4%; P<.0001).¹⁷  Poor adherence to therapy for osteoporosis has been found to be associated with smaller improvements in BMD, less effective suppression of bone turnover markers, and greater risk of fractures.^3,18  In a healthcare claims study involving 58,109 patients with osteoporosis receiving drug therapy for that condition (hormone replacement therapy [HRT], bisphosphonates, or raloxifene), less than 25% of patients persisted on their initial therapy after 1 year.¹⁹  Compliance significantly reduced the risk of hip fracture (odds ratio = 0.382; P<.0001) and vertebral fracture (odds ratio = 0.601; P<.05). In addition, patients who were adherent to therapy for 1 year or more had significantly lower healthcare costs for physician services (by $56; P<.0001) and hospital care (by $155; P<.01).¹⁹

There is evidence that persistence for bisphosphonates is improved with less frequent dosing. Persistence, defined as time to discontinuation, with weekly bisphosphonate treatment was compared with daily dosing in a large retrospective database analysis of women aged 50 years or older (N=211,299).²⁰  Over half of patients in the weekly group (54.6%) remained persistent on therapy after 1 year compared with a little more than a third (36.9%; P<.0001) of patients in the daily bisphosphonate group (Figure 4).²⁰  Similarly, in another review of a healthcare claims database, persistence was significantly improved among patients receiving once-weekly bisphosphonate therapy (n=731) compared with patients receiving once-daily therapy (n=2010) [226.8 days to discontinuation vs 185.2 days; P≤.0001].²¹  In the once-weekly dose group, 44.2% of patients remained on therapy after 12 months, compared with 31.7% of patients in the once-daily group. Although both of these studies demonstrate improved persistence with less frequent dosing, persistence remained suboptimal, with only about half of patients remaining on weekly therapy. Clearly, there is a need to implement effective strategies to improve adherence and persistence to osteoporosis therapies.

Summary

Although awareness of osteoporosis has increased and effective treatments are available, many patients are not being diagnosed and treated. Among patients who are treated, adherence remains suboptimal despite the less frequent (weekly) dosing of available therapies. The results of poor adherence to therapy are higher rates of bone turnover, lower BMD, and increased risk of fractures with their associated clinical consequences and increased costs of healthcare for both the patient and for society. There is a need to educate patients and healthcare providers regarding the burden of osteoporotic fractures, and to develop strategies to encourage healthy lifestyles and improve adherence to osteoporosis therapy.

Table 1: Independent Risk Factors for Hip Fracture (other than BMD)⁹

Risk Factor

Age ≥80 years

History of maternal hip fracture

Any fracture (except hip) since age 50

Current weight < weight at 25 years of age

Height at age 25 ≥168 cm

Self-rated fair, poor, or very poor health

Previous hyperthyroidism

Current use of long-acting benzodiazepines

Current use of anticonvulsants

Current caffeine intake >2 cups/day

No walking or exercise

On feet ≤4 hours/day

Inability to rise from chair without use of arms

Lowest quartile (SD>2.44) depth perception

Lowest quartile (≤0.70 unit) contrast sensitivity

Resting pulse rate >80 beats/minute

Lower calcaneal bone density

SD = standard deviation.

Figure 1: Number of clinical risk factors increases hip fracture risk.⁹

Adapted with permission from Cummings SR et al. New Engl J Med. 1995;332:767-773.
Copyright © 1995 Massachusetts Medical Society. All rights reserved.

Figure 2: The 10-year hip fracture probability at which intervention becomes cost effective, based on all osteoporotic fractures and excluding additional costs of added life-years.¹¹

Figure 3: Prevalence of osteoporosis by diagnosis and by BMD.¹³

NHANES = National Health and Nutrition Examination Survey.
*Data from NHANES through 2002; patient self-reported physician diagnosis of osteoporosis.

Figure 4: Patients remaining on therapy after 1 year.*²⁰

*Percent of patients on therapy defined as having at least 1 day of medication supply in the month.
CURRENT APPROACHES TO THE MANAGEMENT OF OSTEOPOROSIS

John P. Bilezikian, MD

Osteoporosis is characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility and an increased risk of fractures, particularly of the hip, spine, and wrist. Such fractures are often the first symptom of the disease, which may have existed silently for years. The goals of therapy for osteoporosis are to prevent bone loss, to increase bone density and other skeletal properties, and to reduce fracture risk. While pharmacological approaches are important, prevention of osteoporotic fractures should also include nonpharmacological approaches such as lifestyle and diet modifications and measures to reduce the risk of falling.

Nonpharmacologic Approaches

Adequate intake of calcium and vitamin D is important for both the prevention and treatment of osteoporosis.²² Lifestyle changes such as smoking cessation and reducing alcohol and caffeine consumption, if either is excessive, can all have a positive impact on skeletal health. Exercise, especially weight-bearing exercise, and steps to reduce the risk of falls are also important in the overall management of osteoporosis. These nonpharmacological approaches should always be emphasized, even before any discussion of pharmacologic intervention ensues.²²

Pharmacologic Approaches

Numerous pharmacologic treatments for osteoporosis are available in the United States, and additional therapies are available in other countries as well. These treatments may have characteristics that differentiate them from each other such as their routes of administration (oral, intranasal, intravenous, subcutaneous); frequency of dosing (daily, weekly, monthly, quarterly); efficacy; and safety and tolerability profiles.

Estrogen, taken alone or in combination with progesterone in a hormone replacement therapy regimen, is indicated for the relief of the symptoms of estrogen deficiency and the prevention of osteoporosis in those with no contraindications.²²  Although the data from the Women’s Health Initiative showed clear evidence for efficacy to reduce vertebral, nonvertebral, and hip fractures, the adverse events associated with estrogen from that trial have considerably reduced enthusiasm for estrogen as a treatment for osteoporosis.

Raloxifene is a selective estrogen receptor modulator (SERM) that is indicated for the prevention and treatment of osteoporosis. The pivotal clinical trial with raloxifene showed a reduction in the incidence of vertebral fractures, but there was no evidence for nonvertebral or hip fracture protection.^23,24  Raloxifene, given orally on a daily basis, is generally well tolerated, but there is an associated increased incidence of venous thromboembolic events. Hot flashes and myalgias can also occur. Recent studies have demonstrated reduced risk of invasive breast cancer but an increase in the incidence of fatal strokes. Although raloxifene favorably alters the lipoprotein profile in the circulation, coronary events were not shown to be reduced in a recent study.²⁵

The currently available bisphosphonates—alendronate, risedronate, and ibandronate—are the most commonly prescribed agents for osteoporosis. All have proven efficacy for reducing the risk of vertebral fractures. Alendronate and risedronate have also been shown to be effective at nonvertebral sites^26-31 and specifically at the hip.  Bisphosphonates reduce bone resorption and thus favorably alter the bone remodeling cycle. They are generally well tolerated, convenient, and affordable. Alendronate is administered orally on a weekly basis. Risedronate is also available as a weekly oral tablet and, recently, in an oral formulation that is given on 2 successive days once a month. Ibandronate is administered once monthly in its oral formulation and quarterly in its intravenous form. Side effects with the oral bisphosphonates are limited to occasional upper gastrointestinal symptoms due to direct local irritation of the esophageal or gastric mucosa, and an acute-phase reaction when used intravenously. This acute-phase reaction, characterized by fever and myalgias, is very uncommon and usually limited to the day after administration. Osteonecrosis of the jaw, an uncommon event when intravenous bisphosphonates are used in connection with malignancies, is exceedingly rare when bisphosphonates are used to treat osteoporosis. The bisphosphonates are clearly a major therapeutic class for the treatment of osteoporosis. Despite their widespread use, safety, and general effectiveness, they have little, if any, effect to improve certain skeletal properties such as microarchitecture.

Anabolic Agent Parathyroid Hormone

The only agent shown thus far to enhance the microarchitecture of bone by stimulation of bone formation is human parathyroid hormone (PTH).³² In the United States, this agent is available as the N-terminal 34-amino acid fragment (PTH 1-34; teriparatide); in Europe, the full-length molecule (PTH 1-84) is also available. Both forms of PTH stimulate bone formation and, secondarily, bone resorption.^32,33  By stimulating processes associated with bone formation first, with bone resorption following, PTH appears to create an anabolic window during which bone formation predominates. The therapeutic effects of teriparatide are exemplified by a study by Dempster et al involving men and postmenopausal women with osteoporosis.³²  Paired biopsies were obtained before and after treatment with teriparatide, for 18 months in the men with idiopathic osteoporosis and for 36 months in the women with osteoporosis. An analysis of bone structure using high-resolution microcomputed tomography (micro-CT) showed that treatment with teriparatide produced improved trabecular architecture, increased connectivity density, and increased cortical thickness (Figure 1).³²

In the pivotal clinical trial in postmenopausal women with advanced osteoporosis, teriparatide, administered subcutaneously at 20 µg/day, was shown to decrease the risk of one or more new vertebral as well as nonvertebral fractures as compared with the placebo group by 65% and 53%, respectively.³⁴  Further analysis of this trial showed that teriparatide was equally effective irrespective of the number or severity of preexisting fractures. This contrasts with the placebo group in which the number or severity of preexisting fractures was associated with increasing risk of subsequent fractures.³⁵  Teriparatide has also been shown to reduce back pain in women with osteoporosis.³⁶

Anabolic Window

As indicated earlier, PTH stimulates bone formation as well as bone resorption (bone remodeling). Markers of bone formation are increased much more quickly than markers of bone resorption. This pattern suggests that PTH is first stimulating bone formation and thus causing an "anabolic window" to appear. During this window of time, before bone resorption is stimulated to a substantial degree, PTH is maximally anabolic (Figure 2).³⁷

Combination Therapy

The rationale for combination therapy is suggested by the mechanism of action of the  2 main classes of drugs: the antiresorptives and the anabolic agent PTH. The antiresorptives inhibit bone resorption, while PTH stimulates bone formation. If these  2 classes of drugs are used together, one might expect that there would be additive benefits since 2 different therapeutic mechanisms are being utilized.

Black et al addressed this possibility in a study that utilized the combination of alendronate, as the antiresorptive, and PTH 1-84, as the anabolic.³⁸  This well-controlled, double-blind, double-dummy trial enrolled 238 postmenopausal women at risk for osteoporosis (T-score <–2.5, or <–2.0 plus an additional risk factor) who had not previously been treated with bisphosphonates. Patients were randomized to receive 100 µg/day PTH 1-84, or alendronate 10 mg daily, or a combination of the 2 treatments for 12 months.  All subjects received calcium and vitamin D supplements. The greatest improvement in volumetric BMD, as determined by quantitative computed tomography (QCT) of the spine was observed in the group that received PTH 1-84 alone. The increment in volumetric BMD increase with PTH 1-84 alone was approximately twice as great as that observed with combination therapy or alendronate alone (25.5% for PTH 1-84 vs 12.9% for combination and 10.5% for alendronate [P≤.01 for both comparisons]). The data for the hip were similar although not as dramatically different and did not reach statistical significance.³⁸

This study also examined markers of bone turnover, including N-propeptide of type 1 collagen (P1NP), a marker of bone formation, and serum C-terminal telopeptide of type I collagen (CTX), a marker of bone resorption.³⁸  As expected, treatment with PTH 1-84 was associated with a large and rapid increase in P1NP followed by a rise in CTX (Figure 3).³⁸ Combination therapy was associated with a small increase in P1NP at 1 month, followed by a major decline. CTX fell virtually immediately with combination therapy. The reductions in bone turnover markers with combination therapy were very similar to the reductions seen with alendronate alone and dramatically different from the increases in bone markers after PTH 1-84 alone. The results suggest that when this form of combination therapy is used to treat osteoporosis, the effects of alendronate predominate.

These findings do not rule out the possibility that a different antiresorptive in combination with PTH could still produce the hypothesized additive effects of combination therapy. With this in mind, Deal et al investigated combination therapy with raloxifene and teriparatide.³⁹  After 6 months of treatment, the effects on bone formation as measured by levels of P1NP between the combination treatment group and the teriparatide-alone group were similar and positive, indicating that the addition of raloxifene did not impair the actions of teriparatide to stimulate bone formation.³⁹  In contrast, the combination of raloxifene and teriparatide was associated with a reduction in the bone resorption marker, CTX, suggesting that raloxifene was mitigating the action of teriparatide to stimulate bone resorption. This combination then allows teriparatide to stimulate bone formation unimpeded while dampening the action of teriparatide to stimulate bone resorption. One would predict, therefore, that these actions would widen the anabolic window. In fact, bone density increased significantly more (P=.04) in the combination raloxifene and teriparatide group at the hip than in the teriparatide alone group.

How Long Should Patients Stay on Medications for Postmenopausal Osteoporosis?

A key question in the management of osteoporosis in postmenopausal women is how long patients should continue on a particular therapy. Evidence from clinical trials in osteoporosis with virtually all agents that are available indicates that much of the gain in BMD occurs early, with smaller or no increases after the first 3 to 4 years.^40,41 If effects on BMD, a surrogate marker, suggest that the duration of action is limited, they also raise questions as to whether discontinuing therapy might be associated with a loss of fracture protection. Another point with regard to the bisphosphonates is that they are able to sustain the reduction in bone turnover markers if the correct dosing regimen is adhered to. This property is believed to be essential for their therapeutic efficacy. If the bisphosphonate is discontinued and the bone turnover markers begin to rise, would this signal loss of fracture protection? With great affinity for bone, the bisphosphonates have half-lives that can be measured in years. With such long residence in bone, is there prolonged protection even after discontinuation? Are there concerns associated with such long-lived drugs in bone? For PTH, the effect on bone density plateaus over time and bone markers may fall. Other therapies, such as HRT, carry concerns for side effects with long-term therapy.

Issues regarding long-term use of alendronate were addressed in the Fracture Intervention Trial Long-Term Extension (FLEX) trial, an extension of the Fracture Intervention Trial (FIT).⁴¹  Women in the FIT trial were eligible for the FLEX trial if they were in the drug-treatment arm. There was an open-label period between the end of FIT and the beginning of FLEX that averaged 2 years.⁴¹  Most women received open-label alendronate during this time.⁴⁰  The women who met eligibility requirements were randomized to receive alendronate 10 mg/day, alendronate 5 mg/day, or placebo for 5 additional years.

Those who received alendronate in the FLEX study demonstrated a 55% reduction in risk of clinical vertebral fracture compared with the placebo group (2.4% vs 5.3%, respectively; RR=0.45; 95% CI 0.24-0.85).  However, there was no difference in nonvertebral fractures between the alendronate and placebo groups.⁴²  Compared with the long-term alendronate groups, BMD at the hip, femoral neck, and forearm declined gradually but significantly after Year 5 in the placebo group (Figure 4).⁴³  However, BMD at the lumbar spine, trochanter, hip, and total body remained above baseline at Year 10. Markers of bone remodeling similarly rose after alendronate was discontinued, but did not return to pretreatment values over the 10-year evaluation period.⁴³  The results of the FLEX study are not straightforward. Clinical fracture protection appears to require continued use of alendronate, arguing that for global fracture protection alendronate should be continued. On the other hand, there may be downsides to continuing a potent antiresorptive agent such as alendronate indefinitely. Odvina et al⁴⁴  reported on 9 patients who began to fracture after being on alendronate for more than 5 years. In some cases, these individuals received estrogen therapy, another antiresorptive, or had been treated with a glucocorticoid, an agent that could compound the actions of alendronate and reduce the rate of bone formation. Given the number of individuals who have been treated with bisphosphonates and the rarity of isolated reports of “frozen bone” syndrome, it appears to be an exceedingly rare event, if it occurs at all. Recker et al have demonstrated by histomorphometry evidence for bone remodeling even after 10 years of continuous bisphosphonate therapy.⁴⁵ The practical message is that patients on alendronate might be given a “drug holiday” for 1 year after 5 years of therapy. Most experts would favor resuming bisphosphonate therapy after a 1-year drug holiday. Another approach is to check bone turnover markers after 5 years of bisphosphonate therapy and temporarily discontinue therapy only if bone turnover is markedly suppressed.

Length of treatment with PTH is not as controversial as with bisphosphonates because most registration authorities recommend a duration of 2 years (in the United States) or 18 months (in Europe and other counties). The recommendation for this relatively short period of time is most likely because the major clinical trials with PTH were conducted for no more than 2 years. It is therefore unclear whether longer treatment with PTH would have additional benefits.

Safety and Tolerability Profiles

No drug is without safety and tolerability concerns. Estrogen may increase the risk of breast cancer, stroke, and venous thromboembolism.⁴⁶  Venous thromboembolism is also a concern with raloxifene, as is risk of fatal stroke. In addition, raloxifene is associated with an increased incidence of hot flashes.⁴⁷

As noted above, the most common complaint with the use of oral bisphosphonates is esophagitic symptoms, which are mainly manifested as a kind of heartburn. Other concerns such as oversuppression of bone turnover ("frozen bone" syndrome[see above]) and osteonecrosis of the jaw (ONJ) are rare. Osteonecrosis of the jaw is discussed in more detail in the following section. Intravenous (IV) formulations of bisphosphonates are occasionally associated with transient acute-phase reactions, including fever, chills, and flulike symptoms. These symptoms are self-limiting and generally last no more than a day.

Osteonecrosis of the Jaw

Osteonecrosis of the jaw is defined as a lesion of oral mucosa in which either maxillary or mandibular bone is exposed without evidence of healing for 8 weeks. It usually occurs in patients on bisphosphonates after major dental procedures such as extractions.^{48 49} A very controversial subject is whether there is a causal relationship between the use of bisphosphonates and ONJ. Woo et al conducted a systemic review of bisphosphonate-associated ONJ from 1966 through 2006.⁵⁰  The association between ONJ and bisphosphonates was greatest, but still small, in individuals with multiple myeloma or breast cancer who were being treated with IV bisphosphonate (pamidronate or zoledronate). The protocol for intravenous bisphosphonate use in cancer is about 10 times higher than the dose of bisphosphonate for osteoporosis. Even so, the incidence was only 4% to 7%. Some studies have placed the incidence at an even lower percentage. Only 5% of the subjects who were reported to have developed ONJ had osteoporosis or Paget’s disease of bone and were being treated with oral bisphosphonates. Estimates of risk to patients taking bisphosphonate for a nonmalignant indication, such as osteoporosis, are as low as 0.7 cases per 100,000 person-years of exposure.⁵¹  The American Society for Bone and Mineral Research (ASBMR) recommends a comprehensive oral evaluation and any necessary dental procedures in subjects who are going to receive intravenous bisphosphonates in connection with a malignancy.⁵²  Considering the rarity of ONJ when oral bisphosphonates are used for osteoporosis or Paget's disease, the task force does not recommend any special or preliminary dental examination in these patients.⁵²  It is not necessary to discontinue oral bisphosphonates before minor dental procedures, but some physicians will temporarily discontinue bisphosphonate use before major dental procedures (eg, implants). Given the rarity of ONJ in patients treated for osteoporosis, the benefits of bisphosphonates clearly outweigh the risks.

The prescribing label for teriparatide in the United States carries a black box warning for osteosarcoma owing to an increased incidence in rats. It is unclear how this risk relates to osteosarcoma in human subjects since the rats were exposed to much higher doses (3 to 58 fold) and for much longer periods of time (about 75 human-year equivalents). Among more than 300,000 patients who have received teriparatide since 2002, there has been one poorly documented case of osteosarcoma.⁵³  Since the incidence of osteosarcoma in the general population is 1 in 250,000, this rate of osteosarcoma is consistent with epidemiologic expectations.

Summary

Currently, there is a range of agents available for the treatment of osteoporosis that are effective, well tolerated, and have a favorable safety profile. In many cases, these agents have demonstrated beneficial actions on different components of the bone remodeling cycle: resorption, formation, or both. Serious side effects are uncommon with any of these agents.

Figure 1: Paired biopsy specimens from a 64-year-old woman before and after treatment with PTH, viewed by high-resolution microcomputed tomography. Both images are shown at the same magnification. Cortical thickness increased from 320 to 420 µm, and connectivity density increased from 2.9 to 4.6/mm³.³²

Reprinted with permission from Dempster DW et al. J Bone Miner Res. 2001;16:1846-1853.

Figure 2: The anabolic window for PTH: a kinetic model.³⁷

Adapted with permission from Girotra M et al. Arq Bras Endocrinol Metab. 2006;50:745-754.

Figure 3: Median percent changes in serum concentration of markers of bone formation.³⁸

ALN = alendronate; CTX = C-terminal telopeptide of type 1 collagen;
P1NP = N-propeptide of type l collagen; PTH = parathyroid hormone.
Adapted with permission from Black DM et al. N Engl J Med. 2003;349:1207-1215.
Copyright © 2003 Massachusetts Medical Society.  All rights reserved.

Figure 4: Mean percent change in BMD at the hip.⁴³

ALN = alendronate; BMD = bone mineral density; SE = standard error of the mean.
Adapted with permission from Bone HG et al. N Engl J Med. 2004;350:1189-1199.
Copyright © 2004 Massachusetts Medical Society. All rights reserved.

REACHING NEW HEIGHTS IN THE TREATMENT OF OSTEOPOROSIS

Paul D. Miller

Current therapies for osteoporosis are generally well tolerated and effective. However, they are not without drawbacks. Oral bisphosphonates, although highly effective, are poorly absorbed and adhere strongly to food and other medications. Therefore, it is necessary for patients to take these agents after an overnight fast, and at least half an hour before eating or drinking anything other than water,⁵⁴ a regimen that can be cumbersome for patients. Although oral bisphosphonates are generally well tolerated, they have been associated with gastrointestinal side effects, including nausea, dyspepsia, and esophageal irritation. Furthermore, there are some patients who would not be considered appropriate for oral bisphosphonates, such as those with esophageal disease, including scleroderma, achalasia, or Barrett's esophagus.⁵⁵

A range of nonoral formulations of osteoporosis treatments is available. These include the intravenously administered bisphosphonates (ibandronate, zoledronic acid (ZA), and pamidronate), the subcutaneously administered parathyroid hormone (PTH) fragment teriparatide, and calcitonin-salmon, available as nasal spray or parenteral formulation. In addition, new therapies are on the horizon, including denosumab, the human monoclonal antibody (mAb) to the receptor activator of nuclear factor-kB ligand (RANKL), to be administered subcutaneously; the full-length PTH 1-84, currently registered in Europe; as well as PTH in nasal, inhaled, or transdermal formulations.

Ibandronate

Intravenous (IV) formulations of the bisphosphonates avoid the uncertainties of bioavailability with oral bisphosphonates and are dosed much less frequently, 2 characteristics that may be preferred by patients. Ibandronate was the first IV bisphosphonate approved for the treatment of postmenopausal osteoporosis, and is dosed at 3 mg IV every 3 months. Similar to the weekly and the monthly oral bisphosphonates, ibandronate IV was registered not on the basis of proven fracture risk reduction but rather by demonstrating noninferiority to daily oral ibandronate using bone mineral density (BMD) as a surrogate marker end point.

In the Dosing Intravenous Administration (DIVA) Study, 1395 postmenopausal women with osteoporosis were randomized to receive intermittent IV injections of ibandronate (2 mg every 2 months or 3 mg every 3 months) or daily oral ibandronate 2.5 mg (the fracture-proven daily dose) for 2 years.^56,60  The primary end point was the change from baseline in lumbar spine BMD. As shown in Figure 1, both IV regimens were noninferior and in fact were statistically superior compared with the oral regimen at Year 1 and Year 2 (P<.001 for all comparisons).⁵⁶  Serum levels of C-terminal collagen 1 telopeptide (CTX), a marker of bone resorption, decreased to a similar degree with oral or IV alendronate over the 2-year period (data not shown).

Zoledronic Acid: The HORIZON Pivotal Fracture Trial

Intravenous ZA is the first IV bisphosphonate to have registration data based on prospective fracture data, obtained in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly Pivotal Fracture Trial (HORIZON-PFT).⁵⁷  The objective of this trial was to evaluate the potential of once yearly IV ZA 5 mg to decrease fracture risk in postmenopausal women with osteoporosis over 3 years of treatment.

Subjects in HORIZON-PFT were postmenopausal women between 65 and 89 years of age who had a femoral T-score of ≤-2.5, with or without a vertebral fracture; or a femoral-score of ≤-1.5 with at least 2 mild vertebral fractures or 1 moderate vertebral fracture.⁵⁷  Patients were stratified based on whether they were taking nonbisphosphonate osteoporosis medications at baseline: patients in stratum 1 were not taking any osteoporosis medications at baseline and patients in stratum 2 were taking at least one nonbisphosphonate medication. Patients who had previously taken bisphosphonates could join the trial in either strata after a prospectively determined wash-out period, based on duration of prior therapy. Prior use of PTH was not allowed in the trial.⁵⁷

Patients were randomized to receive a 15-minute IV infusion of ZA 5 mg or placebo at baseline, at 12 months, and at 24 months.⁵⁷  The primary end points were new vertebral fractures in stratum 1 and hip fracture in either strata. Secondary end points included any nonvertebral fracture, any clinical fracture, and clinical vertebral fracture, as well as changes in BMD, and changes in markers of bone turnover. Follow-up visits occurred at 6, 12, 24, and 36 months.⁵⁷

Results

A total of 7765 women (mean age 73 years) were randomized, 3889 to receive ZA and 3876 to receive placebo. In each treatment group, 79% of the patients were in stratum 1 and 21% were in stratum 2.⁵⁷

After 3 years, there was a 70% reduction in the risk of morphometric vertebral fracture in the ZA group compared with the placebo group in stratum 1 (3.3% vs 10.9%; P<.001; RR=0.30 [95% CI, 0.24-0.38]) [Figure 2].⁵⁷  At 1 and 2 years, the risk reduction was 60% and 71%, respectively. The cumulative risk of hip fracture was reduced by 41% with ZA treatment in strata 1 and 2 combined (2.5% in placebo group and 1.4% in ZA group; P=.002; hazard ratio = 0.59; 95% CI, 0.42-0.83).⁵⁷  All other secondary end points for fracture—including nonvertebral fractures, all clinical fractures, and clinical vertebral fractures—were significantly reduced at 3 years with ZA compared with placebo (P<.001 for all comparisons). Furthermore, patients in the ZA group had significantly less mean height loss than patients in the placebo group (-4.2 mm vs -7.0 mm; P<.001).⁵⁷

Zoledronic acid also produced significant improvements in BMD at the lumbar spine (6.71% increase), hip (6.02% increase), and femoral neck (5.06% increase) compared with placebo (P<.001, for all comparisons).⁵⁷  Markers of bone turnover, including serum CTX [Figure 3], N-propeptide of type 1 collagen (P1NP), and bone-specific alkaline phosphatase, were significantly decreased in the ZA group compared with the placebo group (P<.001 for all comparisons).⁵⁷  As shown in Figure 4, the levels of CTX remained consistently suppressed during the year following ZA injection.⁵⁷

Intravenous Bisphosphonate Safety

Acute Phase Reaction

The acute phase reaction has been observed with high doses of bisphosphonates, even after larger doses of oral bisphosphonates, but particularly after IV administration. This reaction consists of pyrexia, a flulike illness, and myalgia that occurs within 1 to 2 days of the injection and then resolves after approximately 1 to 2 days. It occurs more commonly after the initial dose and less frequently after subsequent injections.^56,58

In the DIVA study, the incidence of acute phase reaction-like events occurred after the initial ibandronate infusion was higher in the groups receiving IV treatment than in the oral treatment group. Acute phase reactions were generally mild to moderate in intensity, transient in nature, and resolved without any treatment. Most cases of the flu-like illness occurred during the first year.^58,59

In HORIZON-PFT, the rate of acute phase reaction-like events was similarly higher only after the initial injection of ZA and decreased substantially after subsequent injections (Figure 4).⁶⁰

The acute phase reaction is likely due to lysis of peripheral T-lymphocytes.⁶¹  The reaction is self-limiting, with a usual duration of 1 to 2 days, and has no clinical sequelae. Laboratory tests, including liver function, white blood cell counts, and sedimentation rates, remain normal during a reaction.³¹  Furthermore, there are anecdotal reports that the severity of the reaction can be mitigated by premedicating the patient with extra-strength acetaminophen approximately 2 hours prior to injection.

Renal Safety

There have been reports of decreased renal function associated with IV bisphosphonates and very rare occurrences of renal failure.^31,62  Therefore, assessment of renal function is recommended before administration of IV bisphosphonates.^31,63

In the trial of ZA for Paget's disease, the effects of treatment on serum creatinine levels were measured 9 to 11 days after injection. This time range was chosen since an effect of bisphosphonates on renal function will usually become evident within a matter of days due to acute tubular necrosis.⁶⁴  In this study, there was no change in serum creatinine levels from baseline over the time period examined.

In HORIZON-PFT, serum creatinine was also measured 9 to 11 days after infusion. In the ZA group, 1.3% of patients had an increase of serum creatinine >0.5 mg/dL compared with 0.4% of patients in the placebo group (P<.001). Within 30 days, more than 85% of patients had returned to serum creatinine levels within 0.5 mg/dL of preinfusion levels.⁵⁷  There was no difference in renal function as assessed by serum creatinine clearance between the ZA and placebo groups over the 3 years of treatment, as shown in Figure 5.⁶⁵

Cardiac Safety

Another potential concern with IV bisphosphonates is cardiac safety with regard to atrial fibrillation. In HORIZON-PFT, serious atrial fibrillation was more common in the ZA group compared with the placebo group (1.3% vs 0.5%; P<.001).⁵⁷  This effect has not been observed consistently in other trials of ZA or other bisphosphonates.  In a subset of 559 patients who underwent electrocardiography (ECG) before and 9 to 11 days after the third infusion, atrial fibrillation was detected in 2.1% of patients in the ZA group and 2.8% of patients in the placebo group. Additionally, the rate of other ECG abnormalities was not significantly different between the treatment groups.⁵⁷

Bone Safety

Bone safety was also monitored in HORIZON-PFT. There were 2 possible reports of osteonecrosis of the jaw, one in the ZA group and one in the placebo group. Both cases were subsequent to surgical procedures, and both resolved with antibiotic therapy and debridement. There were 7 reported cases of avascular necrosis of the hip or knee, 4 in the ZA group and 3 in the placebo group. There was no adverse effect of ZA on fracture healing. There were 3 cases of nonunion: 2 in the ZA group and 1 in the placebo group.⁵⁷

Denosumab

Denosumab (AMG 162) is a fully human monoclonal antibody to the receptor activator of RANKL. The RANKL, which is expressed by osteoblastic stromal cells, binds to receptor activator of nuclear factor-kB (RANK) and plays a key role in osteoblast differentiation and activation, leading to bone resorption.^66,67  Denosumab inhibits osteoclast formation function and survival (Figure 6).⁶⁶  Denosumab is an IgG₂ immunoglobulin isotype, which has a long half-life and allows for subcutaneous (SC) injection of this agent every 3 to 6 months.

The effect of denosumab on BMD was evaluated in a randomized, controlled phase 2 trial in 412 postmenopausal women with osteoporosis.⁶⁸  Women were eligible if they had lumbar spine T-score of -1.8 to -4.0 or a femoral neck or total hip T-score of -1.8 to -3.5. Other osteoporosis medications were excluded.  Subjects were randomized to receive SC denosumab either every 3 months (at a dose of 6, 14, or 30 mg) or every 6 months (doses of 14, 60, 100, or 210 mg), open-label oral alendronate (70 mg/week), or placebo. The primary outcome was the percent change in lumbar spine BMD at 12 months. Secondary end points included changes in bone turnover.⁶⁸

At 24 months, denosumab given every 6 months was associated with a mean increase in lumbar spine BMD of 4% to 8% in the different dosage groups, compared with an increase of just over 6% for alendronate and a decrease of approximately 1% in the placebo group (P<.001) [figure 7].⁶⁹ Hip BMD was also significantly increased with denosumab (range of 2.5% to 5%) compared with alendronate (3.5% increase) and placebo (-1.8%; P<.001). At all skeletal sites evaluated, increases in BMD were significant compared with placebo (P<.001). Serum CTX, a marker of bone resorption, was rapidly and markedly reduced with denosumab. At the lowest doses of denosumab, this effect was partially reversible. At higher doses, however, CTX remained suppressed over the 24-month treatment period. Denosumab was generally well tolerated, with adverse events similar between the treatment arms. A phase 3 study is ongoing to evaluate the potential for denosumab to reduce the risk of fracture in postmenopausal women with osteoporosis.⁶⁹

Summary

In conclusion, the parenteral routes of administration for osteoporosis therapies offer some distinct advantages over oral formulations, including more reliable drug delivery to the bone and the potential for reduced gastrointestinal side effects. There are advantages and disadvantages for each of the parenteral therapies for osteoporosis. Among the bisphosphonates, IV ibandronate was registered on the basis of a noninferiority surrogate marker study, whereas IV ZA has direct evidence of fracture risk reduction compared with placebo control. Intravenous bisphosphonates have good safety and tolerability profiles. Changes in renal function are minimal in predefined populations when the dose is administered properly. Subcutaneous denosumab is a promising therapy for postmenopausal osteoporosis with impressive reductions in BMD and bone turnover.

Figure 1: Lumbar spine BMD changes in DIVA study.^56,60

BMD = bone mineral density; DIVA = Dosing Intravenous Administration.
*P<.001 versus 2.5 mg daily oral ibandronate.

Figure 2: Incidence of morphometric vertebral fractures at Years 1, 2, and 3.⁵⁷

Figure 3: Mean serum CTX over time.⁵⁷

CTX = c-telopeptide of type 1 collagen.
Adapted with permission from Black DM et al. N Engl J Med. 2007;356:1809-1822.
Copyright © 2007 Massachusetts Medical Group.

Figure 4: Postdose symptom occurring within 3 days after infusion.⁵⁷  (Novartis, data on file)

Figure 5: Long-term changes in CrCl versus baseline during treatment with ZA. ⁶⁵

Months

CrCl = creatinine clearance; ZA = zoledronic acid.

Figure 6: Denosumab mechanism of action.⁶⁶

CFU-M = colony forming unit - megakaryocyte; OPG = osteoprotegerin;
RANK = receptor activator of nuclear factor-κβ; RANKL = RANK ligand.

Figure 7: Mean changes in BMD at the lumbar spine.⁶⁹

ALN = alendronate; BMD = bone mineral density; DEN = denosumab.
Adapted with permission from Lewiecki EM et al. J Bone Miner Res. In press.

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