Pharmacologic Management of Osteoporosis: Current Trends and Future Prospects
Hosam K. Kamel, MD

Dr. Kamel is in the Division of Geriatric Medicine, Nassau County Medical Center, East Meadow, New York, Clinical Campus, State University of New York at Stony Brook. Address for correspondence: Hosam K. Kamel, MD, Division of Geriatric Medicine, Nassau County Medical Center, 2201 Hempstead Turnpike, East Meadow NY 11554.

Osteoporosis is a significant health problem in the elderly population and has been associated with substantial morbidity and disability. Over the past decade, there have been major advances in the pharmacologic management of osteoporosis. Drug therapies are currently available that can inhibit bone loss and promote bone formation, with other approaches under investigation. This article reviews the therapeutic modalities available for the management of osteoporosis and their impact on fracture risk.

(Annals of Long-Term Care 1998;6[12]:382-388)

Pharmacologic management of osteoporosis centers on several therapeutic modalities currently available. Current modalities include hormone therapy, calcium, vitamin D, bisphosphonates, calcitonin, and sodium fluoride. Future agents investigated for the treatment of osteoporosis include parathyroid hormones and anabolic agents (Table).

Hormone Replacement Therapy

Because hormonal deficiencies result in significant bone loss, a discussion of the pharmacologic management of osteoporosis should begin with the available hormone replacement therapies for osteoporosis, including the administration of estrogen, estrogen analogues, and androgens.

Estrogen

Estrogen deficiency at any age is associated with an increase in bone loss.1 Both cross-sectional and longitudinal data present evidence for an increase in the rate of bone loss following menopause or ovariectomy, with effects appearing to be greater in the axial than in the peripheral skeleton.2 Although the precise mechanisms involved in the pathogenesis of this bone loss are not completely understood, it is clear from published evidence that estrogen governs skeletal cytokines, and that with the depletion of this hormone, upregulation of several key signal molecules results in accelerated bone resorption. Conversely, estrogen replacement therapy (ERT) suppresses bone resorption and prevents bone loss by suppressing cytokine activation, thereby slowing the remodeling cycle.3

The loss of bone after menopause follows an exponential pattern.4 Most bone is lost during the first three to six years after menopause,5,6 but some loss related to low estrogen levels may continue for up to 20 years.4 Estrogen replacement therapy has proven to be very effective in preventing postmenopausal bone loss. The beneficial effects of estrogen on bone mineral density (BMD) have been documented by numerous placebo-controlled trials, especially in the early postmenopausal period.7-11 Probably the strongest evidence to date that estrogen prevents bone loss comes from the Postmenopausal Estrogen/Progestin Interventions trial,12 which involved 875 women less than 10 years after menopause in a three-year multicenter, randomized placebo-controlled study. In this trial, women were assigned to one of five treatment regimens: (1) placebo; (2) conjugated equine estrogen (0.625 mg/dL); (3) conjugated equine estrogen plus cyclic progesterone (10 mg/day for 12 days each month); (4) conjugated equine estrogen plus medroxyprogesterone (2.5 mg/day continuously); or (5) conjugated equine estrogen plus micronized progesterone (20 mg/day for 12 days each month).

Spine BMD increased 5% and hip BMD increased 2% in women receiving unopposed estrogen. The addition of progesterone did not change BMD response compared with estrogen alone. Although there is likely to be a skeletal dose response to estrogen (the higher the dose, the greater the increase in BMD), the data from this study strongly support the notion that low doses of conjugated equine estrogen (0.625 mg/day) can preserve BMD in postmenopausal women. More recently, Genant and colleagues13 reported that esterified estrogens at a dose of 0.3 mg per day produced positive bone and lipid changes without inducing endometrial hyperplasia. Estradiol administered in a percutaneous patch for transdermal absorption (0.05 micrograms twice a week),14 or as estradiol implants (50 mg six times monthly),15 is also effective in preventing bone loss.

Estrogen administered soon after menopause prevents the early phase of bone loss16 and decreases the incidence of subsequent osteoporosis-related fractures.17,18 The use of estrogen during only the early postmenopausal period, however, appears to be inadequate. A study of older women from the Framingham observational group found that previous use of estrogen was not protective against fractures of the hip that occurred 10 to 20 years following the termination of treatment.19 Only use of estrogen for more than seven years was found to be protective.19 Lindsay et al20 demonstrated that the cessation of ERT that had begun at menopause led to accelerated bone loss comparable to that observed following menopause. Thus, for maximal protection against osteoporosis, ERT should be administered for at least 20 years, and perhaps indefinitely.21

Now that there is evidence to suggest that the administration of estrogen for 15 years or more may increase the risk of breast cancer,22 the question that remains is whether 15 years of ERT started immediately after menopause would be sufficient to protect against later fracture. Critical evidence is not yet available to make that judgment, although the results from the Study of Osteoporotic Fractures Research Group23 would tend to argue against discontinuation of ERT if prophylaxis against hip fracture is a principal endpoint of therapy.24

Another important question is when to start ERT. Lindsay et al25 originally demonstrated that oophorectomized women who were started on estrogen more than six years after surgical menopause had preservation of bone mass but did not regain lost bone. The evidence from several recent controlled trials, however, supports the capacity of estrogen to halt, or even reverse, bone loss, even when started 20 years after menopause.18,26 In one of these trials, the administration of estrogen replacement therapy to elderly postmenopausal women resulted in a 5% to 10% increase in vertebral BMD.20

Estrogen is usually given in combination with a progestin to decrease the risk of endometrial cancer. The exception is for women who have undergone a hysterectomy, where estrogen is given alone. Current evidence does not definitively answer questions about the skeletal effects of progesterone. Previous controlled trials have demonstrated that progesterone combined with estrogen offers no advantage over estrogen alone in terms of preserving bone mass12 or protecting against osteoporosis22 after menopause. However, several small and poorly controlled trials with progesterone alone during menopause suggest a possible protective effect against postmenopausal bone loss.

Estrogen Analogues

Estrogen analogues are agents that possess varying degrees of estrogen-like activity and, therefore, mediate changes similar to those of estrogen on bone. The three estrogen analogues currently available for clinical use are tamoxifen, tibilone, and raloxifene. Others are under investigation.

Tamoxifen. Tamoxifen is a synthetic antiestrogen currently approved in the United States as an adjuvant therapy in the treatment of breast cancer in postmenopausal women.21 Studies of postmenopausal women treated with tamoxifen demonstrated a partial protective effect on the skeleton. Love et al,27 in a two-year randomized, double-blind, placebo-controlled trial, studied the effects of tamoxifen on BMD in 140 postmenopausal women with breast cancer. In women given tamoxifen, the mean BMD of the lumbar spine increased by 0.61% per year, whereas in those women given placebo, it decreased by 1% per year (P < 0.001). Radial BMD decreased to the same extent in both groups.

Tamoxifen also was found to increase high-density lipoprotein (HDL) cholesterol, sex hormone binding globulin, and T4 binding globulin. Tamoxifen also simultaneously decreases low-density lipoprotein cholesterol in breast cancer patients, suggesting that it has an estrogen-like effect on the liver. Major side effects from tamoxifen include hepatic toxicity, endometrial hyperplasia, and venous thrombophlebitis.21

Tibilone. Tibilone is a synthetic steroid with mixed properties of estrogen, progestin, and androgen. Because of its estrogenic properties, it relieves menopausal symptoms and decreases bone resorption. However, due to its progestogenic and androgenic properties, it has a reduced effect on stimulating endometrial proliferation. Thus, uterine bleeding should occur much less frequently, and the occurrence of endometrial cancer presumably should be very low.28çTibilone, in general, appears to be similar to estrogen in its effects on bone. Tibilone’s main advantage over cyclic therapy with estrogen and progestin appears to be the lower incidence of vaginal bleeding and breast tenderness.29 The major disadvantage of tibilone therapy compared with ERT is its less favorable effect on the serum lipid profile.30 Several investigators demonstrated that long-term tibilone therapy is not associated with a decrease in low-density lipoprotein (LDL) cholesterol as occurs with ERT. Tibilone maintains or reduces the levels of HDL cholesterol, whereas oral ERT increases it.31 Like estrogen, however, tibilone reduces the serum concentration of lipoprotein (a), an independent risk factor for coronary artery disease.32 Overall, however, tibilone would be expected to afford less protection against coronary artery disease than does estrogen.28 Tibilone is currently approved for clinical use in several European countries, but not in the United States.

Raloxifene. Raloxifene is one of a new class of agents, called selective estrogen receptor modulators (SERMs). These agents have the unique property of acting as estrogen agonists in bone and liver and as pure estrogen antagonists in uterine tissue.32 Delmas and colleagues,33 in a double-blind, placebo-controlled, two-year trial, evaluated the effect of three doses of raloxifene (30-mg, 60-mg, or 150-mg doses) on BMD in a group of 601 postmenopausal women. All subjects also received 400 mg to 600 mg of elemental calcium per day. Results from this study showed dose-related increases in BMD measurements at the lumbar spine, hip, and femoral neck in the raloxifene group compared with subjects who received placebo.

Similarly, Heaney and Draper,34¥using calcium kinetics, demonstrated a 28% reduction in bone resorption by raloxifene. The effect of raloxifene on bone density in older women was evaluated in a randomized prospective study involving 51 older postmenopausal women (mean age, 64.4).35 Results from this study showed that 60 mg per day of raloxifene for six months was less effective than 0.625 mg per day of conjugated estrogens in increasing BMD in the lumbar spine (1.3% versus 3.2%). Raloxifene, however, tended to be more effective than conjugated estrogen at the femoral neck (2.8% versus 1.6%). The effect of raloxifene on fracture risk is not yet known.

A pooled analysis of data from several clinical trials showed that raloxifene was generally well tolerated. The majority of adverse events were mild and did not necessitate discontinuation of therapy. Adverse events considered to be related to raloxifene treatment included hot flushes, leg cramps, and increased risk of venous thrombosis, particularly during the first four months of treatment.36 The long-term safety and effectiveness of raloxifene have not been established. The Food and Drug Administration (FDA) recently approved usage in the United States of 60 mg per day of raloxifene for the prevention of osteoporosis in postmenopausal women.37

Androgens

Skeletal effects of androgen deficiency are well established in animals. Androgen deficiency in both young and old rats causes increased bone turnover, which can be prevented with androgen replacement.38 In humans, hypogonadism is regarded as a major risk factor for osteoporosis in men.39 Hypogonadism may also be prevalent in elderly men with osteoporosis. It is not clear, however, whether a gradual and partial decrease of sex hormone concentrations in elderly men lowers their bone density or increases their risk for fracture. A threshold concentration for serum testosterone associated with increased risk of osteoporosis is, indeed, not established.

Whether androgen replacement therapy could prevent bone loss in elderly men (as established for estrogen replacement in women) is still not clear, although androgen replacement may decrease bone resorption.40 Testosterone has also been shown to reduce the risk of glucocorticoid-induced osteoporosis in men of all ages on long-term prednisone treatment.41 Moreover, testosterone replacement in hypogonadal and elderly men may have a beneficial effect on lipid metabolism through decreasing total cholesterol and the atherogenic fraction of LDL cholesterol.42

Calcium

Calcium is a substrate for bone mineralization that has an antiresorptive effect on bone through its suppressive effect on parathyroid hormone (PTH) secretion.43 Studies in women within the first five years of menopause show that calcium supplementation has a consistent positive response on BMD in sites rich in cortical bone, such as the proximal radius.44 At the more trabecular spine site, calcium induces an initial increase in bone density through closure of remodeling space, although there is little evidence to date that it provides cumulative benefit after the first year of treatment.

This transit effect appears significant, however, in view of the recent finding of Recker et al 45 that supplemental calcium reduced spine fracture rates. Studies in late postmenopausal women showed similar effects of calcium supplementation on BMD.46 The groups with the lowest calcium intake appear to benefit most from added calcium. Chapuy et al47 were able to show 43% reduction in hip fractures and 32% reduction in nonvertebral fractures in elderly community-dwelling subjects treated for 18 months with 1.2 grams of elemental calcium and 800 IU of vitamin D. The results from this study are remarkable and emphasize the importance of calcium and vitamin D supplementation in the elderly population.

A National Institutes of Health Consensus Development Conference panel in June 1994 considered a calcium intake of 1500 mg per day to be optimal for postmenopausal women not taking estrogen, and 1000 mg per day optimal for women on hormone replacement therapy.48 Both of these figures are higher than 800 mg per day, the current recommended dietary allowance for adult women. Middle-aged and elderly men have not been studied extensively; men with lower calcium intakes may benefit from supplemental calcium, but this remains to be determined.44

Vitamin D

Vitamin D is one of the primary regulators of calcium homeostasis in the body and is critically important for normal mineralization of bone. The active hormone, 1,25 (OH)2 D, is produced by sequential hydroxylation of vitamin D in the liver (25-hydroxylase) and in the kidney (1 a-hydroxylase). To provide a substantial amount of calcium and phosphorus for bone mineralization, 1,25 (OH)2 D acts on the intestine to enhance absorption of these minerals. Several potential mechanisms have been put forward to explain the role of vitamin D in the development of osteoporosis. There appears to be an age-related decline in renal 1,25(OH)2D production, attributable in part to diminished renal response to PTH,49 as well as a decrease in the renal 1a-hydroxylase enzyme, which is needed for the production of 1,25 (OH)2 D.50 Further, aging is associated with decreased cutaneus synthesis of vitamin D after sunlight exposure, as well as decreased hepatic conversion of vitamin D to 25 (OH) D. Evidence also exists that with age intestinal mucosal cells become relatively resistant to the effect of 1,25 (OH)2 D, thus impairing intestinal calcium absorption. All of this is compounded by the fact that elderly individuals are in a low–vitamin D state secondary to inadequate diet and decreased exposure to sunlight.47

Vitamin D supplementation has been shown to improve calcium balance in individuals with vitamin D deficiency. In addition, vitamin D may positively influence bone density in healthy individuals who do not have vitamin D deficiency or osteoporosis by suppressing PTH activity. This may be especially important during the winter months in which lower levels of vitamin D and higher levels of PTH have been shown to coincide with an increased prevalence of osteoporotic fractures.51

Cholecalciferol, 25 (OH) D, is the parent vitamin D compound and is the most widely prescribed by physicians because it is inexpensive and safe. Calcitriol, 1,25 (OH)2 D, is the active vitamin D metabolite. Calcitriol, in addition to its action on the intestine to stimulate calcium absorption, may also stimulate osteoblast activity.52 Treatment with calcitriol has been shown to reduce bone loss,53 and in some studies to increase bone mass.54 In contrast to the parent vitamin D, the margin between ineffective doses of calcitriol and those that induce hypercalcemia or hypercalciuria is relatively narrow. Calcitriol analogues with greater margins of safety in laboratory animals have been developed. One of these analogues, alfacalcidol, has been studied recently in a prospective, randomized study involving 66 postmenopausal women with osteoporosis. Alfacalcidol has been shown to prevent further bone loss with minimal side effects.55 Further clinical trials of these agents in women with osteoporosis are in progress.

Bisphosphonates

Bisphosphonates are carbon-substituted analogues of pyrophosphates and endogenous physiologic inhibitors of bone mineralization.56 They were initially developed as inhibitors of growth and dissolution of calcium crystals but were subsequently found to inhibit osteoclast-medicated bone resorption.57,58 Until recently, etidronate was the only available oral bisphosphonate in the United States. In the clinical trials that evaluated etidronate in the treatment of osteoporosis, it was found that the dosage of etidronate that inhibits bone resorption also impairs the mineralization of newly synthesized bone matrix, making long-term continuous administration not feasible.57 Clinical trials in which etidronate was given cyclically rather than continuously showed promising results.52 In two of these trials, an intermittent regimen of two weeks of etidronate, followed by 11 to 13 weeks of calcium supplementation alone, led to a small increase (about 2.5% per year) in spinal bone mass and may also have decreased occurrence of vertebral fractures during the first two years of treatment.59,60 Etidronate is not approved for treatment of osteoporosis in the United States by the FDA.

Alendronate, another oral bisphosphonate, was recently approved by the FDA for usage in the United States for prevention of osteoporosis. Trials involving alendronate showed that it is more potent yet causes less inhibition of mineralization than etidronate.5 In vitro experiments showed that the dose of etidronate needed to inhibit osteoclasts is 6000 times more than the required dose of alendronate. Alendronate can therefore be administered at relatively low dosage, a property that benefits its safety profile. In a multinational trial, a total of 994 postmenopausal women with osteoporosis (defined by bone density of 2.5 standard deviations below the mean for young women) received either placebo or one of two regimens of alendronate: 5 mg or 10 mg a day for three years; or 20 mg a day for two years, followed by 5 mg a day for a third year.61 All subjects also received calcium supplementation in the form of calcium carbonate to provide 500 mg a day of elemental calcium. Overall, treatment with alendronate was associated with a 48% reduction in new vertebral fractures (3.2% versus 6.2% in the placebo group, P = 0.03), a decreased progression of vertebral deformities (33% versus 41% in the placebo group, P = 0.028), and a reduced loss of height (P = 0.005). In general, alendronate was well tolerated.

The more recent Fracture Intervention Trial62ýprovided further evidence to support the effectiveness of alendronate in preventing fractures in postmenopausal women with osteoporosis. In this study, 2027 postmenopausal women (age 55 to 81) with low femoral neck BMD and existing vertebral fracture ìere randomized to receive either alendronate or placebo and were followed up for approximately three years. In this study, there was a 47% reduction in new vertebral fractures in the alendronate group compared with the placebo group.

Hosking and colleagues,63 in a randomized controlled trial involving 1174 postmenopausal women under 60 years of age, demonstrated that alendronate prevents early postmenopausal bone loss to nearly the same extent as estrogen-progestin therapy. Alendronate appears to continue to work even after it is no longer being administered. Rossini et al 64 demonstrated that the positive effects of alendronate on lumbar spine BMD did not change up to 12 months after the cessation of treatment. Similarly, Stock et al 65 demonstrated that the positive effects of alendronate on bone density were maintained up to two years after discontinuation of the drug.

ýThe most common toxicity of alendronate is on the esophagus and stomach, where it may cause direct irritation and ulceration. To avoid this complication, it is recommended that the patient take the drug with a full glass of water and remain upright forøat least a half hour to avoid having the pill lodge in the esophagus. This procedure may prove to be difficult to implement in the nursing home due to the limited availability of staff members to ensure proper compliance with this recommendation.

Calcitonin

Calcitonin can be used to treat osteoporosis, although patients who have osteoporosis do not appear to have a deficiency of this hormone. Calcitonin has been shown to have analgesic properties and is currently used by many clinicians for the short-term amelioration of pain associated with fractures due to osteoporosis.66 Calcitonin mostly affects trabecular bone with minimal effect on cortical bone, which limits its usefulness in Type II (senile) osteoporosis. The effect of calcitonin on the incidence of fractures is currently being evaluated. Calcitonin has been shown to be a safe alternative for the treatment of osteoporosis in women who cannot take estrogen.67 Women who have high-turnover osteoporosis or who have pain because of a recent vertebral fracture are likely to benefit most from its use.

Salmon calcitonin is much more potent than human calcitonin, but its use may lead to resistance associated with increased titers of antibodies that neutralize calcitonin. In a study by Muff et al,68 resistance occurred in six to 19 patients within 15 months after the beginning of treatment. The incidence of this resistance can be decreased by using human calcitonin, although non–antibody-related resistance, possibly related to receptor down-regulation, may still occur. Resistance to salmon calcitonin is less frequent when it is given in lower doses, administered intranasally, and not given continuously.57

Until recently, salmon calcitonin was available only by subcutaneous or intramuscular injections in the United States. Intranasal salmon calcitonin has been shown by several investigators to be effective and safe for the prevention of bone loss in postmenopausal women with reduced bone mass.69 Intranasal salmon calcitonin also possesses analgesic effects similar to those of the other forms. Salmon calcitonin administered by nasal spray (200 IU per day) has been recently approved by the FDA for prevention and treatment of osteoporosis in the United States.

Sodium Fluoride

Sodium fluoride is the only agent now available that can stimulate osteoblastic proliferation and function and increase bone formation.64 When sodium fluoride is used to treat osteoporosis, there is a continuous increase in bone mass of the spine.70 In some series, this increase in bone mass is accompanied by a decreased incidence of spinal fractures.71 However, the therapy may result in an increased risk of fracture of the hip as well as other nonvertebral fractures.57 Even in series in which a satisfactory effect of sodium fluoride is observed, some patients do not respond. Some patients do develop side effects, including knee and ankle pain attributed to microfractures; other patients cannot tolerate the drug because of nausea. An oral slow-release form is better tolerated with fewer gastrointestinal and rheumatic complications.

Pak et al72ýrecently reported that patients with postmenopausal osteoporosis treated with slow-release sodium fluoride had a lower rate of vertebral fractures and a higher fracture-free rate (defined as the absence of fractures during the trial) compared with a group of controls who had received calcium. A substantial increase in the bone mass of the lumbar vertebrae of 4% to 5% per year for four years, an average increase in the bone density of the femoral neck of 2.4% per year, and no change in the bone density of the radial shaft were observed in patients who had received sodium fluoride. The frequency with which minor side effects and appendicular fractures occurred was similar in the two groups. The authors concluded that slow-release sodium fluoride and calcium citrate administered for four years inhibits new vertebral fractures, augments spinal and femoral neck bone mass, and is safe to use.

In any case, calcium supplements, with or without vitamin D, are necessary to prevent bone mineralization defects that accompany the use of sodium fluoride alone. Currently, the use of sodium fluoride in the United States is considered experimental, although this may change in the near future. A slow-release sodium fluoride preparation has been recommended for approval by an FDA advisory committee. Various formulations of sodium fluoride have been available in Europe for this indication for many years. The ideal role for sodium fluoride in the future may be to augment bone density at the initiation of therapy before switching to antiresorptive agents for the long-term maintenance of bone density.

Future Therapy

A number of new agents are currently being investigated for the prevention and treatment of osteoporosis. These include new anabolic agents, such as strontium, parathyroid hormone peptides, and analogues. In addition, efforts are underway to improve the formulations or regimens of existing agents.73

Conclusion

ýlthough much remains to be learned about the causes and management of osteoporosis, there is sufficient knowledge now to undertake therapeutic action. At the present time, hormone replacement therapy with estrogen, in addition to ensuring adequate calýium and vitamin D intake, remains the method of choice for the prevention of postmenopausal bone loss. For those women who cannot take estrogen, raloxifene and alendronate appear to be reasonable alternatives. Alendronate may be added for women with low baseline BMD, or if the BMD continues to fall significantly while the patient is on estrogen or raloxifene. Calcitonin may help patients who have pain because of an osteoporosis-related fracture. Based on ongoing clinical trials, fluoride may play a role in the treatment of osteoporosis in the near future. Based on this progress, the means may soon be available to bring this public health problem under control.

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Annals of Long-Term Care - ISSN: 1524-7929 - Volume 6 - Issue 11 - November 1998