SEARCH

SEARCH BY CITATION

Keywords:

  • bone mineral density;
  • fracture;
  • osteoporosis;
  • postmenopausal;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACOLOGICAL TREATMENT
  5. NON-PHARMCOLOGICAL TREATMENT
  6. CONCLUSION
  7. REFERENCES

Treatment of osteoporosis has advanced dramatically during the past decade, with more therapeutic options than ever now available. Large-scale randomized placebo-controlled trials have documented the efficacy of a number of agents in reducing vertebral and non-vertebral fractures. Anti-resorptive agents (hormone replacement therapy, selective estrogen-receptor modulators, calcitonin and bisphosphonates) and bone-forming anabolic agents (parathyroid horomone and strontium ranelate) act via different mechanisms to reduce fractures and improve bone strength. In view of the high prevalence of calcium and vitamin D insufficiency in Asia, calcium and vitamin D supplementation remains a fundamental part of any treatment regimen, especially among the elderly. Given the high cost of these agents, a global assessment of the fracture risk of the patient is essential to determine the need for pharmacological treatment versus life-style modification and dietary supplementation in the management of postmenopausal osteoporosis in Asia.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACOLOGICAL TREATMENT
  5. NON-PHARMCOLOGICAL TREATMENT
  6. CONCLUSION
  7. REFERENCES

Treatment of osteoporosis has advanced dramatically during the past decade, with more therapeutic options than ever now available. A large number of bone-active agents have been widely used across Asia, but prescribing practices vary greatly between countries. Nonetheless with a lack of comparative studies, the most effective treatments for osteoporosis have yet to be determined. The choice of agent is influenced by its effectiveness, but also other considerations such as side-effects, cost and availability.

The primary goals of osteoporosis management are to prevent fractures and to stabilize or increase bone mass and bone strength in individuals with or at risk of osteoporosis. Osteoporosis is defined operationally by bone mineral density (BMD): the fracture risk increases as BMD decreases. Adult bone mass is a culmination of the peak bone mass attained in young adulthood and the subsequent loss of bone tissue that occurs with ageing or due to other secondary causes. Maximizing peak bone mass and minimizing the rate and duration of bone loss are likely to be a cost-effective approach in most areas of Asia. This can probably be achieved by targeting younger people in whom the short-term fracture risk is low and promoting a diet that has adequate calories, protein, calcium and vitamin D combined with a lifestyle that incorporates weight-bearing exercise and avoidance of smoking and alcohol. Pharmacological intervention will nonetheless often be indicated in those at high risk of fracture, and should be mandatory in patients who have had a previous fracture, including subclinical morphometric vertebral fracture. Women with a BMD T-score < –2.5 should receive medical therapy. For subjects with BMD T-score between –1 and –2.5, need for treatment will depend on the number and severity of clinical risk factors.1,2

Current pharmacological therapies can be classified depending on their mode of action: the antiresorptive (anticatabolic) agents and the bone-forming (anabolic) agents. The former agents act mainly by reducing bone resorption and rate of bone remodeling. Calcium, vitamin D, estrogen/hormone replacement therapy (HRT), selective estrogen-receptor modulators (SERMs), calcitonin and bisphosphonates all belong to this category. Bone-forming agents act mainly by stimulating new bone formation. Parathyroid hormone (PTH) and teriparatide (PTH 1-34) belong to this category. The newly available agent strontium ranelate has probable dual antiresorptive and bone-forming action.

PHARMACOLOGICAL TREATMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACOLOGICAL TREATMENT
  5. NON-PHARMCOLOGICAL TREATMENT
  6. CONCLUSION
  7. REFERENCES

Estrogen/hormonal replacement therapy

Estrogen was a conventional agent for osteoporosis treatment and many observational studies have demonstrated its antifracture effect. Nonetheless observational studies suggest that long-term treatment is required as the benefit of fracture prevention rapidly wears off once estrogen is withdrawn. Estrogen returns bone turnover to premenopausal levels by its action on the osteoblasts and osteoclasts, and maintains a positive calcium balance through its effect in the intestine and kidney. The chance of osteoporotic fractures has been shown to be lower in women exposed to estrogen therapy for more than 7 years compared with a nonexposed group.3

The Women's Health Initiative (WHI) study, a large randomized and controlled trial involving 16,000 postmenopausal women, confirmed that estrogen or estrogen plus progestogen reduce vertebral and hip fracture risk by 33%. Unfortunately, the side-effects of breast cancer, stroke and heart attack, and venous thromoembolism outweigh the benefit of fracture reduction.4,5 Even in the estrogen-alone arm, an increased risk of stroke was observed although the reduction in hip fracture risk was again confirmed.6

At present, estrogen/HRT is no longer considered appropriate for the long-term treatment of osteoporosis. The use of HRT is now limited to the short-term prevention of osteoporosis and moderate to severe climacteric syndrome in the early menopausal period. The estrogen dose should be titrated according to the individual clinical response. For osteoporosis treatment, other modalities of intervention should be carefully considered. If a patient chooses to continue HRT, they should be adequately counseled about the long-term risks and benefits.

Selective estrogen-receptor modulators

Selective oestrogen-receptor modulators (SERMs) are non-steroidal compounds with tissue-specific estrogen agonist and antagonist actions. Raloxifene, the only SERM currently available, is approved for prevention and treatment of postmenopausal osteoporosis. It is a benzothiophene derivative that is a non-hormonal agent that adheres to the estrogen receptor with high affinity, but exhibits estrogen-agonistic effects on bone and estrogen-antagonistic effects on the endometrium and breasts. Raloxifene increases BMD at the spine and hip by 2.7% and 2.4%, respectively.7 It reduces vertebral fractures by 30–50%8 but the effect on hip and non-vertebral fractures has not been proven except in high-risk subjects. Its safety and efficacy in prevention of postmenopausal bone loss, increased BMD and suppression of biochemical markers of bone turnover has been confirmed in Asian women.9

Raloxifene has additional extraskeletal benefits: it reduces the risk of invasive breast cancer, in particular estrogen-receptor positive breast cancer, and lowers serum LDL-cholesterol. Raloxifene thus represents an alternative to conventional HRT in prevention of osteoporosis. It is mostly prescribed to reduce vertebral fracture risk in younger postmenopausal women who develop bone loss predominantly at the spine but not the hip. Although the side-effects of raloxifene are minimal compared with those associated with HRT, patients may also experience hot flushes, leg cramps, fluid retention and venous thromboembolism.

Calcitonin

Calcitonin is a natural polypeptide hormone secreted by the thyroid gland with antiresorptive effects on the osteoclasts. It can be administered by subcutaneous or intramuscular injection or as a nasal spray. During the 5-year prevent recurrence of osteoporotic fractures (PROOF) study, calcitonin administered as a 200-IU per day nasal spray reduced the risk of new vertebral fractures by 33%. A similar risk reduction was observed in those with a pre-existing vertebral fracture.10 The effect of nasal calcitonin treatment on non-vertebral and hip fracture risk reduction was nonetheless small, regardless of dose. Hence, calcitonin is seldom used as the first-line agent but provides an alternative to bisphosphonates or SERMs when they are not tolerated or are contraindicated. In the acute stage following an osteoporotic fracture, calcitonin may be prescribed for its analgesic effect, achieved via an inhibitory action on the central nervous system.11 Apart from rhinitis and local irritation, nasal calcitonin has no serious toxicity.

Bisphosphonates

The mainstay of pharmacological therapy for the prevention and treatment of osteoporosis in both postmenopausal women and men is the bisphosphonates. These drugs adhere tightly to mineralized surfaces and are then ingested by osteoblasts during bone resorption. This results in loss of function and apoptosis of the osteoclasts. With refilling of the remodeling space, secondary mineralization is enhanced and the rate of bone turnover is reduced. The first generation compound is etidronate. The long duration of action of bisphosphonates favours their intermittent use, and these compounds can be administered as a weekly (such as alendronate and risedronate) or monthly oral dose (ibandronate), or intravenously at intervals of 3 (ibandronate) or 12 months (zoledronate). Bisphosphonates reduce vertebral factures by 50–70% and non-vertebral fractures by 30–50% over 3 years, although their antifracture efficacy is evident as early as 1 year after commencement. Apart from increasing BMD and reducing bone turnover, there is some evidence that these compounds increase bone structure and quality which can contribute to fracture risk reduction.12

These compounds are poorly absorbed (≈1–5% with empty stomach) from the enterogastric tract. On rare occasions, they may cause esophageal ulceration. Oral bisphosphonates must be taken with a full glass of water and on an empty stomach. Patients must also remain upright for at least 30 minutes before eating to minimize the risk of esophageal erosion. Infrequent oral dosing and intravenous preparations help to improve adherence and acceptance of treatment. Contraindications include hypersensitivity to bisphosphonate, hypocalcemia and esophageal abnormalities such as stricture or achalasia. They should be used with caution in patients with renal impairment. Concern has recently been expressed about an association of osteonecrosis of the jaw (ONJ) with bisphosphonate treatment. The risk factors for ONJ include the use of chemotherapy for oncological conditions, corticosteroids and periodontal disease. It is not clear whether a lower dose or changing the dosing schedules of bisphosphonates can reduce the incidence of ONJ.13

(i) Etidronate

Etidronate increases lumbar spine BMD by about 5% and decreases vertebral fracture risk by up to 37%.14 The effect on hip fracture has not been documented. Etidronate is given cyclically at a dosage of 400 mg daily for 14 days every 3 months and must be administered in the middle of a 4-h fasting interval. During the etidronate-free periods, calcium and vitamin D supplementation should be given.

(ii) Alendronate

The Fracture Intervention Trial (FIT) study15 examined the effects of alendronate on postmenopausal women with or without pre-existing vertebral fractures. Among those with vertebral fractures and a femoral neck BMD T-score of –1.6 or less, 3 years of alendronate treatment reduced the risk of fractures by 47%, 51% and 48%, respectively, at the spine, hip and wrist. Among those with low BMD but no pre-existing vertebral fracture, alendronate reduced morphometric vertebral fractures by 44%. A meta-analysis involving 12,855 patients also confirmed the reduction of vertebral fracture risk by 50% with alendronate.16 A pooled analysis of six randomized studies of 3723 patients revealed that the incidence of lower arm and non-vertebral fractures was also decreased by approximately 50%. With regard to hip fracture, the integrated data of 11 studies showed that alendronate reduced fracture risk by 40%. Nonetheless it should be noted that the effects were only significant in patients with a BMD T-score below –2.5. Alendronate prevented bone loss and increased BMD at the spine and hip by 5–10% with 3 years of treatment. Comparable increase in BMD of 5.8% at the spine and 3.4% at the hip was also observed with alendronate treatment for 1 year in postmenopausal osteoporotic Chinese women.17 Treatment for 10 years is safe with continual improvement in BMD and fracture efficacy.

(iii) Risedronate

Risedronate increases BMD by 4.5% at the spine and about 3% at the femoral neck with 1.5 to 3 years of treatment.18 At a dose of 5 mg daily, it reduces the risk of fractures of the spine and hip by 30–50%. Integrated results from various studies reveal that risedronate significantly reduces clinical vertebral and non-vertebral fractures as early as 6 months after initiation of treatment.19 Risedronate is mainly effective in patients with BMD T-scores below –2.5, and treatment for 7 years is associated with continuous antifracture efficacy with a safety profile similar to placebo. The 35 mg once-weekly regimen gives similar increases in spine and hip BMD as the daily dosage.20

(iv) Ibandronate

Ibandronate is 1000 to 10,000-fold more potent than etidronate and is effective at less than once per week dosing. The BONE trial21 showed that oral ibandronate, given daily (2.5 mg) or intermittently (dosing-free interval more than 2 months) to postmenopausal women with osteoporosis, significantly reduced 3-year vertebral fracture risk by 52% and 50%, respectively. A subsequent 2-year, multinational, phase III study demonstrated that once-monthly oral ibandronate at a dose of 150 mg was not inferior to a daily oral ibandronate regimen in terms of BMD improvement (6% and 3% BMD gain above baseline at the spine and hip, respectively) and safety profile.22 In the Dosing Intravenous Administration study, no significant difference was found between a 3-monthly intravenous or daily oral regimen.23 Nonetheless the effect of ibandronate on non-vertebral fracture was only seen in post-hoc analysis of high-risk subjects with a previous history of vertebral fracture.

(v) Zoledronic acid

Zoledronic acid is the most potent aminobisphosphonate currently available, and is given as a once yearly intravenous regimen. Zoledronic acid 5 mg once yearly for 3 years reduces the incidence of morphometric vertebral fractures by 70% (RR 0.30, 95% CI: 0.24–0.38), clinical vertebral fracture by 77% (RR 0.23; 95% CI: 0.14–0.37), and hip fracture by 41% (RR 0.59; 95% CI: 0.42–0.83) in postmenopausal women with BMD T-scores < –2.5 with or without a pre-existing vertebral fracture or in those with BMD T-scores < –1.5 with a pre-existing vertebral fracture.24

There is no consensus for the duration of treatment with bisphosphonates, and patients have to be assessed for the degree of BMD improvement and the degree of suppression of bone turnover. In a pragmatic sense, it seems reasonable to assess the need for continued treatment and reappraise a patient's fracture risk after 3–5 years. For those patients with high fracture risk, further reduction in fractures is seen with long-term treatment for up to 10 years. In patients who elect to cease treatment, monitoring for recurrence of bone loss with biochemical markers of bone turnover should determine whether treatment is recommenced.

Some data show that a combination of two antiresorptive agents, such as bisphosphonate with estrogen or bisphosphonate with raloxifene, yields slightly additive effects on BMD. Nonetheless the benefit should be judged in light of the increased cost and potential for side-effects. The combined use of two antiresorptive agents on fracture reduction has not been documented.

Vitamin D analog

Active vitamin D analogs improve bone mass by increasing intestinal calcium absorption. Hydroxylated vitamin D, including 1-alpha cholecalciferol and 1,25-dihydroxy-cholecalciferol, appears to reduce the risk of falls by 20% among ambulatory or institutionalized elderly.25 These compounds are used in some countries with positive results on hip fracture prevention, although the effect on BMD improvement is controversial.26 The effect on fracture reduction is likely to be through falls prevention by improving muscle strength and neuromuscular coordination. The side-effects include hypercalcemia and hypercalciuria.

Parathyroid hormone

Parathyroid hormone (PTH) or teriparatide (1–34 amino-terminal fragment of PTH) is the first anabolic agent for the clinical treatment of osteoporosis. PTH stimulates periosteal and endocortical bone apposition and increases trabecular bone formation. Overall, it increases cortical and trabecular thickness, and bone diameter, and improves bone strength and architecture.27 Teriparatide 20 µg daily subcutaneously has been shown to increase BMD by more than 10% at the spine and 3% at the hip in postmenopausal osteoporotic women. The risk of vertebral and non-vertebral fractures was also reduced by 65% and 54%, respectively.28 The incidence of new vertebral fractures was reduced by up to 90% among those with moderate to severe vertebral fractures. PTH or teriparatide is indicated for severe postmenopausal osteoporosis with high risk of fracture, as well as in patients who already have fractures and are prescribed antiresorptive therapy. Prior use of bisphosphonates may retard the anabolic effect of PTH but has little effect on the overall beneficial effect on BMD. Sequential bisphosphonate therapy is required to maintain BMD for bone loss that appears after treatment cessation. Side-effects are mild and transient and include nausea and orthostatic hypotension. Transient asymptomatic hypercalcemia has also been observed. Prolonged high-dose therapy in rats resulted in an increased risk of osteosarcoma, thus the maximum recommended duration of therapy in humans is 2 years. The cost and need for a daily subcutaneous injection and the concern about long-term safety have limited the widespread use of PTH.

Strontium ranelate

Strontium ranelate is a new agent that possesses antifracture efficacy although its mechanism of action is not fully understood. It appears to possess dual actions in reducing bone resorption and stimulating bone formation. In vitro, it increases osteoblast proliferation29 while reducing osteoclast differentiation. Results show that treatment with oral strontium ranelate at a dose of 2 g daily for 3 years reduced the risk of new vertebral fractures by 41%, hip fracture by 36% and non-vertebral fracture by 19%.30 This agent is effective in both osteopenic and osteoporotic patients. Daily oral therapy is well tolerated without major side-effects. There are no data on the combined use of strontium ranelate with other bone-active agents.

NON-PHARMCOLOGICAL TREATMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACOLOGICAL TREATMENT
  5. NON-PHARMCOLOGICAL TREATMENT
  6. CONCLUSION
  7. REFERENCES

Calcium and vitamin D

Adequate calcium and vitamin D intake plays a fundamental role in the prevention and treatment of osteoporosis. Calcium and vitamin D supplementation have been shown in randomized trials to retard bone loss and bone resorption, reduce serum parathyroid hormone, and increase BMD. The benefits of calcium and vitamin D appear to be more marked in late postmenopausal life and in those with a lower calcium intake. Calcium supplementation in postmenopausal women increases BMD by 1–3%.31 The efficacy of calcium supplementation alone on fracture risk reduction is most convincing in the frail elderly, but the effect in the community-dwelling population is controversial. There is evidence to show that calcium and vitamin D enhance the efficacy of pharmacological agents, hence they play a fundamental role in fracture prevention.

In general, a much lower calcium content of around 400 mg per day is present in the Asian diet compared with a Western diet.32 The prevalence of vitamin D insufficiency has been reported to be around 50% in community-dwelling postmenopausal women, and up to 60–80% in the institutionalized elderly.33 In view of the high prevalence of low calcium intake and vitamin D insufficiency in Asia, increasing calcium and vitamin D intake, either by supplementation or substitution of calcium and vitamin D-rich foods, is likely to be an effective approach to reducing fractures in Asia. The daily recommended intake for adults in Asia is 800–1200 mg/day calcium and 400–600 IU/day vitamin D. For patients with osteoporosis, 600–800 IU vitamin D per day is recommended. The inclusion of advice on avoiding calcium and vitamin D inadequacy in fracture management protocols and fall prevention programs would be a pragmatic approach toward osteoporosis prevention and management in Asia.

Phytoestrogens

Phytoestrogens are natural chemicals found in plants. The two main classes that are of health interest are isoflavones and lignans. Isoflavones are available in beans and soya products such as soya milk or tofu. Lignans are found in ryes, fruits, vegetables and whole grains. Extracted phytoestrogens are also marketed as dietary supplements. Although some preliminary studies reported positive effects of phytoestrogens on BMD and bone markers in Chinese women,34 there is no consistent evidence that they offer a beneficial effect on BMD. There is also no clinical evidence that phytoestrogens in any form reduce the risk of fractures.35

Other measures

This section has dealt mainly with pharmaceutical interventions for fracture prevention and management, but the management of osteoporosis must be more broadly based. Other major aspects include the prevention and treatment of falls, and the use of physiotherapy and physical exercises in patients with established osteoporosis and fractures. Identification of frequent falls and provision of a combined program of muscle strengthening and balance retraining, withdrawal of psychotropic medication, correction of visual deficiency, as well as home hazard modification in association with advice on optimizing medication in preventing further falls, should form an important element of all osteoporosis programs.

CONCLUSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACOLOGICAL TREATMENT
  5. NON-PHARMCOLOGICAL TREATMENT
  6. CONCLUSION
  7. REFERENCES

Although the aim of treatment of postmenopausal osteoporosis is to decrease the susceptibility to fracture, incidence of fracture is influenced by multiple factors. Pharmacological therapy improves bone quality by preventing bone turnover and increasing bone formation, or even both. Non-pharmacological interventions such as calcium and vitamin D supplementation should not be neglected since they play a substantial role in abating fracture risks. Current treatment regimens of postmenopausal osteoporosis should consider several non-pharmacological measures. For instance life-style modification and rehabilitation enhance treatment effect and decrease the risk factors for vertebral and non-vertebral fracture. Ultimately, appropriate drug selection with efficient intervention and monitoring remain the major measures to manage the patient with postmenopausal osteoporosis.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PHARMACOLOGICAL TREATMENT
  5. NON-PHARMCOLOGICAL TREATMENT
  6. CONCLUSION
  7. REFERENCES