Progress in Osteoporosis and Fracture Prevention: Focus on Postmenopausal Women

Kenneth G Saag; Piet Geusens

Disclosures

Arthritis Res Ther. 2009;11(5):251 

In This Article

Advances in Osteoporosis Pharmacotherapy: More than a Decade of Progress

Beyond the need for sufficient calcium, vitamin D, and exercise, the past decade has seen an emergence of new data supporting a growing armamentarium of therapeutics for osteoporosis. Pharmacological therapies useful in the prevention and treatment of osteoporosis affect bone remodeling by either inhibiting bone resorption or enhancing bone formation. The majority of the agents currently licensed in both the US and other countries inhibit bone resorption. Recombinant PTH (teriparatide), on the other hand, is a bone anabolic agent. Strontium ranelate has a dual effect on bone remodeling: it stimulates bone formation and inhibits bone resorption, as shown in animal models, but is not available in the US. Despite an increasing number of well-designed studies providing evidence for pharmacotherapies in reducing primary or secondary fracture risk, many high-risk patients are not treated,[50] and for patients who initiate therapy, adherence to therapy is commonly below 50% at 1 to 2 years.[51]

Estrogen

Estrogen has a direct effect on bone mass through receptors on osteoclasts and other bone cells and it results in lowered bone turnover and resorption. Observational studies have suggested a 25% to 70% risk reduction for fractures associated with the use of estrogen replacement therapy (ERT).[52–55] Results from the Women's Health Initiative (WHI), a study of over 16,000 postmenopausal women, convincingly confirmed a significant risk reduction of hip fractures attributed to combined conjugated equine estrogen and medroxyprogesterone (RR = 0.66, 95% confidence interval [CI] 0.45 to 0.98)[56] as well as estrogen alone in those women who had undergone hysterectomy.[57] In addition to its beneficial effects on bone, ERT raises high-density lipoproteins and lowers low-density lipids in post-menopausal women.[58,59] Although a number of observational studies, including the Nurses Health Study,[60] have reported a 35% to 80% reduction in cardiovascular events and prolonged survival among women with coronary heart disease compared with nonusers,[61–65] results from the WHI and other studies of both primary and secondary cardiovascular prevention refute this conclusion.[56,62,66,67] Data from the WHI found a nearly 30% increased risk of coronary heart disease and an over 40% increased risk of stroke.

Beyond heart disease, three significant concerns with estrogen are an increased risk of thromboembolic events,[68] hyperplastic effects on the endometrium (potentially leading to endometrial cancer), and a heightened risk for breast cancer. The WHI[56] and other studies[69] have shown a 26% to 35% increased risk of breast cancer. Some,[70] but not all,[71] studies suggest that invasive breast tumors that develop among estrogen users have a more favorable histologic prognosis and that lobular cancer is more common than ductal cancer.[72]

The decision to initiate ERT should be individualized and based on a balanced assessment of risk and benefits by the physician and patient.[73,74] Lower-dose estrogen can increase bone mass, may have a lower adverse effect profile, and raises interest in further study of this possible approach.[75,76] The proven increased risks for breast cancer and hypercoagulability and the higher risks of both primary and secondary cardiovascular disease (at least among older women) offset bone benefits and have substantially diminished enthusiasm for long-term higher-dose estrogen historically used by many patients. Although questions about the relative benefit and risks of different estrogen types, routes of administration (oral versus transdermal), administration protocols (opposed by progestins versus unopposed), and variable risk profiles based on a woman's age and comorbidities persist, current recommendations support restricting the use of estrogen in most women to the perimenopausal period[77,78] and not with the primary aim to prevent fractures in the context of treatment of osteoporosis. Furthermore, the growing array of alternative bone-directed medications now available further restrict the estrogen niche.

Selective Estrogen Receptor Modulators

Selective estrogen receptor modulators (SERMs) are non-steroidal synthetic compounds that have estrogen-like properties on the bone and cardiovascular systems yet are estrogen antagonists to the breast and, in some cases, the endometrium. The first SERM developed both for breast cancer prevention and for osteoporosis, raloxifene, is now licensed in many countries for osteoporosis.[79] After 3 years of follow-up in the Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter study of over 7,700 postmenopausal women with at least one vertebral fracture or osteoporosis on the basis of a T score of −2.5 or below, 60 mg/day of raloxifene reduced vertebral fracture risk by 30%.[80] This decline in fracture risk at the spine was of a magnitude similar to that seen with more potent antiresorptive agents such as the aminobisphosphonates and emphasized the importance of attenuation of bone turnover, in addition to effects on BMD, for fracture risk reduction.[81,82] Similar to tamoxifen, the risk of invasive breast cancer was decreased by 72% during the MORE study,[83,84] particularly among women with higher estradiol levels.[85,86] Hot flashes and other menopausal symptoms may recur on raloxifene. Also similar to estrogen, with raloxifene, there is an increase in lower-extremity edema as well as a roughly threefold increased risk of deep venous thrombosis.[80] Additional SERMs, such as bazedoxifene and lasofoxifene, are under development. Bazodoxifene decreases vertebral fracture risk to a degree similar to that of raloxifene (approximately 40% over a 3-year period[87]) and, in a post hoc analysis, reduced the risk of nonspine fractures in a subgroup of patients with high risk for fractures based on the FRAX algorithm.[2] Preliminary results from the PEARL (Postmenopausal Evaluation And Risk reduction with Lasofoxifene) trial showed significant reductions compared with placebo in vertebral and nonvertebral (but not hip) fracture risk as well as in estrogen receptor breast cancer with the 0.5 mg dose.[88] This is the only SERM, to date, that has primary data on nonvertebral fracture risk reduction. Of potential concern, a small rise in overall mortality was reported in the 0.25 mg dose but not in the 0.5 mg dose.

Calcitonin

Randomized controlled trials of both injectable[89–91] and intranasal[92–95] calcitonin for treatment of established postmenopausal osteoporosis have consistently shown either stabilization of BMD or small, but significant, increases in vertebral BMD of approximately 1% to 3% on 200 IU daily for over 3 to 5 years. Beneficial BMD effects at the hip have not yet been reported. Modest increases in vertebral BMD with intranasal calcitonin are accompanied by significant declines in biochemical measures of bone resorption.[96] A 5-year multicenter study of 1,255 postmenopausal women showed a 36% reduction in vertebral fractures in the 200 IU, but not in the 100 or 400 IU, dosage group. Interpretation of study results was further limited by an approximately 50% dropout rate.[97,98] Nasal calcitonin is generally well tolerated, with occasional rhinitis. Headache, flushing, nausea, and diarrhea have been reported more commonly with subcutaneous rather than with intranasal calcitonin. On the basis of data that are somewhat weaker than those of osteoporosis drugs (including the absence of data on hip or nonvertebral fracture risk reduction) along with emerging new therapeutic agents, calcitonin has been relegated to a second- or third-line agent for osteoporosis prevention and treatment.

Bisphosphonates

Bisphosphonates are potent inhibitors of bone resorption and fractures when administered orally or by intravenous infusion.[99] Variations in the structure of the amino side chains of these drugs affect their pharmacological activity. All oral bisphosphonates are poorly absorbed, with bioavailability of less than 1%. These agents bind tightly to hydroxyapatite crystals of bone, where they have a variable but generally long skeletal retention (approximately 10 years for alendronate). Over prolonged administration, a regional paracrine effect of continuously deposited and recycled bisphosphonates may partially account for a lack of rapid loss of BMD gains at some, but not all, skeletal sites when these agents are discontinued.[100–102] The nitrogen-containing bisphosphonates (that is, alendronate, risedronate, and zolendronate) have variable affinity for bone and function as antiresorptive agents by variable enzyme inhibition, impairing cholesterol metabolism of the osteoclast and leading to cytoskeletal alterations and premature osteoclast cell death via apoptosis.[103,104]

As a class, oral bisphosphonates may lead to gastrointestinal (GI) intolerance, particularly at low pH.[105] Most reported GI symptoms have been nonulcer dyspepsia, and in most clinical trials, there have not been significant differences between those exposed to bisphosphonates and those receiving placebo.[106,107] There have been rare reports of severe esophagitis[108] and case reports of esophageal cancer in patients taking oral bisphosphonates.[109] Some small studies suggest that GI side effects may be fewer with risedronate than alendronate.[110]

The most common bisphosphonates licensed and used internationally are alendronate, risedronate, ibandronate, and zoledronic acid. These drugs are used in osteoporosis, Paget disease, myositis ossificans progressiva, heterotopic ossification, multiple myeloma, other malignancies with bone metastasis, and hypercalcemia. Alendronate, risedronate, and zoledronic acid have all been shown to improve BMD among patients receiving glucocorticoids.[111–114]

Alendronate was the first aminobisphosphonate approved by the US Food and Drug Administration for the treatment and prevention of osteoporosis. Postmenopausal women receiving 10 mg/day of alendronate showed a lumbar spine BMD increase of 7% to nearly 9% over a 2-year period.[115,116] Smaller, but still significant, changes were seen at the femoral neck and trochanter. In early postmenopausal women, 5 mg/day of alendronate prevented the loss of BMD at the spine, hip, and total body.[117] In a separate study, the 5 mg/day dose prevented bone loss to nearly the same extent as an estrogen-progestin combination (estrogen effect was 1% to 2% greater than 5 mg).[118] Increases in spinal BMD with alendronate continue for up to 7 years of daily therapy.[119] Daily alendronate has a similar benefit and adequate tolerability even among older female residents of long-term care facilities.[120] A once-weekly preparation of alendronate has greatly exceeded daily administration based on BMD efficacy, improved ease of use, and tolerability that is equivalent to or better than daily therapy.[121,122] Among 2,027 older women with at least one prior vertebral fracture and low femoral neck BMD in the Fracture Intervention Trial (FIT), alendronate had significant 47% and 51% reductions in morphometric vertebral and hip fractures, respectively.[123] In FIT subjects without prevalent vertebral fractures, alendronate 10 mg decreased radiographic vertebral fractures by 44%.[124] A multinational study of alendronate similarly identified a 47% risk reduction for nonvertebral fractures.[125] A long-term extension to the FIT study found that, with the exception of clinical vertebral fractures, fracture risk reduction at other skeletal sites was statistically indistinguishable in those receiving 5 years on followed by 5 years off of alendronate versus a full 10 years of therapy.[100] Further preliminary evaluation of these data has revealed that women with a femoral neck BMD T score of −2.5 or below at the 5-year mark had a higher risk of subsequent fractures.[126] Thus, the decision about whether to stop therapy with alendronate after a finite period of time is a topic of current controversy and in need of additional scientific data. In addition to prior duration of therapy, past adherence to therapy informs the risk of subsequent fractures.[127]

Combination approaches of bisphosphonates with either estrogen or SERMs have shown equivalent or better BMD than with either therapy alone,[128,129] although concerns of oversuppression of bone remodeling and potential risk of inadequate repair of bone microdamage persist.[130] Alendronate can attenuate the loss of BMD seen after stopping hormone replacement therapy.[131]

Alendronate clinical trials have shown no significant increases in serious adverse effects or significant GI adverse effects between treatment groups and placebo.[106,132] In a study of glucocorticoid-induced osteoporosis, there was a small increase in nonserious upper GI adverse effects in those taking 10 mg but not 5 mg or placebo.[111] Results of bone histomorphometry indicate that alendronate decreases bone turnover in a dose-dependent manner but does not impair mineralization.[121,133,134]

Risedronate is a pyridinyl bisphosphonate that increases bone mass and prevents fractures.[135] In separate US[136] and multinational[137] VERT (Vertebral Efficacy with Risedronate Therapy) studies, 1,226 and 2,458 postmenopausal women with at least one prior vertebral fracture were treated with 5 mg of risedronate. Women receiving risedronate experienced significantly fewer new vertebral (41% US and 49% multinational) and nonvertebral (39% and 33% reduction, respectively) fractures over a 3-year period.[136] In the Hip Intervention Program study, risedronate 5 mg significantly reduced hip fractures among women with confirmed low bone mass but not among those selected primarily on the basis of fall risks without documented osteoporosis.[138] Similar to alendronate, combined treatment with risedronate and estrogen resulted in additive improvement in BMD and further reduction in bone turnover.[139] Although the increases in BMD seen with risedronate were more modest compared with those of alendronate in one head-to-head comparator study,[140] a fairly similar fracture effectiveness is believed to be due in part to the decrease in bone resorption, as evidenced by significant suppression of biochemical markers.[141,142] Risedronate is taken daily, weekly, or (more recently) monthly and is generally well tolerated, with no significant differences in upper GI adverse events between those receiving placebo and risedronate.[136,143]

Ibrandronate either orally (daily or monthly schedules) or intravenously successfully reduced markers of bone turnover, increased BMD,[144,145] and reduced fractures of the vertebra (relative risk reduction [RRR] = 52%).[146] Secondary analyses of persons in ibandronate studies with initial BMD at or below −3.0 showed that ibandronate had a protective effect on hip fracture risk reduction as well.

Zolendronic acid (zolendronate) is administered as a yearly intravenous infusion and significantly reduced both vertebral (RRR = 70%) and hip (RRR = 41%) fractures in a large multinational study.[147] A subsequent study examined women and men who had experienced a prior hip fracture and showed a significant reduction in subsequent clinical fractures along with a reduction in mortality.[148] Side effects may include an acute-phase response with myalgias and flu-like symptoms in 10% to 15% of patients receiving their first dose. These symptoms most commonly resolve within several days and are attenuated with acetaminophen, prior oral bisphosphonates, and repeated doses of the intravenous therapy. Patients receiving intravenous zoledronic acid must have adequate renal function (creatinine clearance of greater than 30 mL/minute) prior to getting this agent.

On the basis of largely uncontrolled reports of osteonecrosis of the jaw and newer questions about atypical femoral fractures, there is increasing scrutiny of particularly longer-term therapy with bisphosphonates as a class.[149] Osteonecrosis of the jaw has been reported in an estimated 2% of cancer patients receiving higher doses of predominately intravenous bisphosphonates for patients with malignancies in particular.[150] Cases also have been described in patients receiving bisphosphonates for osteoporosis. Although mechanisms are not confirmed for these two adverse outcomes, if a relationship is supported by further studies, this will have further impact on the idea of a 'drug holiday'.[151]

In summary, there have been a large number of studies documenting the efficacy of several bisphosphonates in terms of BMD gains and, of more importance, with regard to reduction of both vertebral and nonvertebral fractures. As a class, bisphosphonates are the most efficacious anti-resorptive agents currently available for bone. Despite a significant duration of worldwide use of bisphosphonates, a number of questions such as the necessary duration of therapy, long-term safety, and use among women of child-bearing potential as well as among children remain.[152]

Parathyroid Hormone

When bone is exposed to elevated PTH levels continuously (e.g., hyperparathyroidism) it acts in a catabolic fashion. In contrast, exogenously administered intermittent PTH is anabolic stimulating skeletal remodeling and raising BMD both in rodent models and in human studies.[153,154] PTH (residues 1 to 34) (teriparatide) significantly decreased the risk of vertebral (65% risk reduction in those on 20 μg/day) and nonvertebral fractures and increased BMD at all sites investigated, except for the radial shaft.[155] As a potential explanation for initial decreases in cortical bone density at sites such as the wrist, PTH initially increases intracortical porosity. It also leads to periosteal new bone formation and increases cross-sectional area, potentially increasing cortical bone strength.[156,157] Teriparatide increases BMD in the spine of men by nearly 6%.[158] There is an enhanced effect on bone mass when PTH is sequentially followed by alendronate[159] or estrogen.[160] When PTH is compared directly with alendronate, there is a greater BMD increase seen with PTH in postmenopausal[161] as well as glucocorticoid-associated[162] osteoporosis. Although BMD increases with PTH occur even in the presence of potent antiresorptive agents such as alendronate,[163] antecedent oral bisphosphonates started concurrently with PTH may attenuate bone mass improvement seen with PTH.[164,165] PTH administered subcutaneously once a day has been associated with asymptomatic hypercalcemia, occasional nausea, and headache. Clinical trials of teriparatide were terminated early by the finding of osteosarcoma in Fisher rats.[155] Selective parathyroid receptor agonists and antagonists are under investigation and may play a future role in osteoporosis.[166] Due in part to the development of osteosarcoma in Fisher rats in the initial fracture trials (leading to their premature discontinuation), teriparatide at 20 μg/day is recommended for only a 24-month administration. It is used most commonly in adults with severe osteoporosis, many of whom have had fractures while on other antiosteoporotic agents or have had intolerance to bisphosphonates.

Strontium Ranelate

Daily intake of strontium ranelate has been shown to reduce the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis or a prevalent vertebral fracture or both. In a post hoc analysis in women over 74 years old with low BMD at the femoral neck, it reduces the risk of hip fractures.[167,168] Fracture reduction was still found after 5 years of treatment.[169] In a post hoc analysis in women older than 80 years, strontium ranelate reduced the risk of vertebral and nonvertebral fractures.[170] Strontium ranelate prevented quality-of-life impairment in postmenopausal women with established vertebral osteoporosis.[171]

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