Once osteoporosis is established there are a number of therapeutic strategies that have been shown to increase bone mineral density and reduce fracture risk (Table Currently available evidence for interventions in osteoporosis).
Table Currently available evidence for interventions in osteoporosis
|Drug||Postmenopausal bone loss
|Fracture risk reduction|
|Calcium and vitamin D||A||ND||A||A|
|Hormone replacement therapy||A||A||A||B|
A, meta-analysis of at least one randomized controlled trial or well-designed controlled study without randomization; B, at least one well-designed other trial type (cohort, case-control or quasiexperimental study); hormone replacement therapy, hormone replacement therapy; ND, not determined.
As rapid loss of bone density occurs as a result of estrogen deficiency in the early postmenopausal years, the use of hormone replacement therapy (hormone replacement therapy) is a rational approach to delaying this bone loss.
Estrogens act on receptors present on both osteoclasts and osteoblasts to suppress osteoclast formation, recruitment and activation. Estrogen deficiency also results in an increased level of cytokines, many of which have adverse effects on bone. Unfortunately the benefits of hormone replacement therapy are lost soon after withdrawal of treatment and the popularity of prolonged treatment with these agents is diminishing in light of recent evidence about long term safety. Nevertheless the recent Women’s Health Initiative trial demonstrated a significant 24% reduction in the risk of osteoporotic fractures as a whole, and specifically a 34% reduction in the risk of hip fracture and a 34% reduction in the risk of spinal fracture. It also showed that hormone replacement therapy can be used cost-effectively in perimenopausal women to reduce fracture rates.
The selective estrogen receptor modulators (selective estrogen receptor modulators), of which raloxifene is the only agent currently available in the UK, have been shown to reduce the rate of vertebral fracture in postmenopausal women with osteoporosis. As yet there is no evidence of any reduction in fracture rate at non-vertebral sites. While raloxifene has been shown to significantly reduce the rate of estrogen-receptor-positive breast cancer during therapy of up to 4 years duration, it does increase the relative risk of venous thromboembolism by the same two- to three-fold as conventional hormone replacement therapy.
Chemical analogs of pyrophosphate bisphosphonates are potent antiresorptive agents. The first agents to be used clinically were the non-nitrogen-containing bisphosphonates etidronate and clodronate. These compounds act by forming a toxic analog of adenosine triphosphate within osteoclasts, reducing the resorptive capacity of the cell and under some circumstances causing cell death. Both agents are effective in the treatment of osteoporosis but are considerably less effective than the newer nitrogen containing bisphosphonates such as alendronate and risedronate.
The nitrogen-containing bisphosphonates act on the 3-hydroxy-3-mefhylglutaryl coenzyme A (HMG-CoA) mevalonate pathway, inhibiting prenylation of specific guanosine triphosphates resulting in osteoclast apoptosis.
Alendronate is available as a 70 mg once weekly dose and daily doses of 10 mg or 5 mg. It has been shown to increase bone mineral density in postmenopausal females and also in males. Anti-fracture efficacy has been demonstrated at the hip, spine and other sites. The magnitude of risk reduction is consistently around 50%. Alendronate has been studied in combination with hormone replacement therapy with greater increases in bone mineral density demonstrated with the combination than with either agent as monofherapy.
Risedronate is now available as a 35 mg once weekly dose and daily doses of 5 mg. It has similar anti-fracture efficacy to alendronate and has been shown to significantly reduce the risk of vertebral fracture within 1 year.
Numerous other bisphosphonates are currently under development including intravenous zolendronate which has been shown to be effective with infusions at 3, 6 and 12-monthly intervals. Oral and intravenous ibandronate has been shown to reduce fracture risk at various dosing schedules, including an intermittent oral dose of 2.5 mg on alternate days for 12 doses every 3 months. The efficacy of bisphosphonates in increasing bone mineral density and reducing fracture risk is clear; continued developments strive to increase the ease of administration and acceptability of treatment.
Calcitonin is a 32-amino-acid peptide produced by the C cells of the thyroid. It is secreted in response to elevated serum calcium levels and binds to osteoclast receptors resulting in inhibition of bone resorption. In addition to its limited role in the management of osteoporosis it is a useful agent in the management of hypercalcemia of malignancy. Calcitonin administered by subcutaneous injection has been shown to increase lumbar spine bone mineral density in late postmenopausal women and reduce the risk of further vertebral fracture in a small study of women who had already sustained more than one vertebral fracture. The use of injectable calcitonin is limited by side-effects including nausea and flushing and reactions at the injection site. Nasal calcitonin has been shown to have some anti-fracture efficacy, but this major study had a discontinuation rate of 59% at 5 years and failed to identify any reduction in fracture risk in the higher-dose treatment arm of the study. Although it is likely that calcitonin reduces vertebral fractures, its effect on non-vertebral fractures remains more uncertain.
Calcium and vitamin D supplementation
As previously discussed, maintaining adequate intake of both calcium and vitamin D throughout life is important in achieving and subsequently maintaining skeletal integrity.
There is some evidence that supplementation of dietary intake with additional calcium (1200 mg per day) and vitamin D (800 IU per day) results in an increase in bone mineral density and a reduction in non-vertebral fracture rate in a population of elderly institutionalized women. A Cochrane review, however, concluded that there was uncertainty as to whether it was calcium, vitamin D or the combination that had a beneficial effect on fracture rates and this has been compounded by a very recent study showing a modest effect of 4-monthly oral vitamin D on fracture rates.
New agents for the treatment of osteoporosis
Parathyroid hormone is the principal hormone in calcium homeostasis in humans. In response to low serum calcium levels parathyroid hormone secretion is increased, enhancing bone resorption and liberating calcium from the skeleton, thus elevating serum calcium. parathyroid hormone induces 1-α-hydroxylase activity in the kidney, increasing the levels of 1, 25-dihydroxy vitamin D3 which increases calcium uptake from the gut and enhances renal tubular reabsorption of filtered calcium. Although persistently elevated levels of parathyroid hormone result in a loss of bone mineral density, there is evidence that pulsed therapy administered subcutaneously on a daily basis has a marked anabolic effect with significant increases in bone mineral density and reduction in fracture risk. In a recent study in women with previous vertebral fracture comparing placebo with either 20 or 40 µg o f parathyroid hormone daily, 14% of the placebo group experienced a further fracture while only 5% of those receiving 20 (µg parathyroid hormone daily and 4% receiving 40 µg daily sustained further fracture, giving a relative risk of 0.35 and 0.31, respectively. The use of parathyroid hormone is likely to be hindered by the considerable cost of treatment and, to a lesser extent, by the inconvenience of subcutaneous administration.
Strontium is a trace element that occurs in small amounts in human tissue. When combined with ranelic acid it inhibits bone resorption and stimulates bone formation by uncoupling the remodeling process. Initial results suggest strontium ranelate is effective at reducing both vertebral and non-vertebral fractures.
Selections from the book: The management of the menopause (2003)