Calcitonin
Calcitonin is a 32-amino acid, single-chain peptide secretory product of neuro-endocrine C-cells located in the human thyroid gland. Calcitonin is a potent inhibitor of osteoclast function. There are two approved dosage forms, injectable (which is rarely used and is associated with nausea, vomiting, and flushing) and a nasal spray. After administration of calcitonin, there is a rapid decrease in bone resorption and hypocalcemia. However, good evidence of antifracture efficacy is difficult to find. Evidence from the Prevent Recurrence of Osteoporosis Fractures (PROOF) study of nasal calcitonin is compromised by the fact that only 378 women completed the study out of 1255 enrolled.¹⁷ In this study, a 400-unit dose of calcitonin nasal spray did not produce a significant reduction in vertebral fractures. Clearly, calcitonin produces a much weaker effect on bone than other agents for osteoporosis management.

Bisphosphonates
Bisphosphonates are synthetic compounds that were initially developed for industrial use, to inhibit the growth of crystals. They were soon discovered to have a number of biological effects, including the ability to inhibit osteoclast-mediated bone resorption. The magnitude of this effect depends on a number of factors, including inherent drug potency, dose, route of administration, and rate of bone turnover.

Alendronate is the most potent drug currently available for the treatment of osteoporosis. The agent was studied in the Fracture Intervention Trial (FIT), a very large, randomized, controlled trial that included 6,459 participants and several years of observation (Table 2).¹⁸ All of the enrolled women had low hip bone mineral density scores (T-scores < -1.6). Women were randomized to receive either 5 mg/day of alendronate or placebo. On the basis of new data indicating improved efficacy on bone mass, the dose was increased to 10 mg after two years. The dropout rate was less than 4%. The women who received alendronate achieved substantial increases in bone mineral density (mean, 7%-9% at the spine and 5%-8% at the hip compared to placebo). Alendronate was also shown in this trial to reduce the risk of hip fracture by 56% by year four in women who had osteoporosis but no prior vertebral fractures. The incidence of new vertebral fractures was reduced by 50%.¹⁸ Meta-analyses of all of the clinical trials of alendronate showed consistent reductions in hip-fracture risk of approximately 50%, as well as significant reductions in the risk of vertebral and wrist fractures.¹⁹

A long-term trial of alendronate showed that spinal bone density continues to increase over time and that bone density increases at other sites are maintained. In addition, discontinuation of alendronate does not appear to be associated with the accelerated bone loss seen in women who discontinue estrogen.²⁰

In over 17,000 patients studied, alendronate has been found to be generally safe and well tolerated. In the FIT study, there were no significant differences between alendronate and placebo in the incidence of adverse effects.¹⁸ Two-year data have shown that once-weekly administration of alendronate 70 mg produces bone density and turnover effects identical to those seen with daily 10-mg doses; this is now the recommended dose. The bisphosphonates must be taken on an empty stomach, first thing in the morning with water only and cannot be followed by any food or drink for at least 30 minutes.



Risedronate is also approved for the prevention and treatment of osteoporosis. Risedronate produces moderate effects on bone mass in both the spine and hip and reduces the risk of fracture throughout the skeleton. The fracture data with this agent derive from three studies; two assessing vertebral fracture and all nonvertebral fractures and one looking primarily at hip fracture. In the two Vertebral Efficacy with Risedronate Therapy (VERT) studies, risedronate reduced the risk of vertebral fractures by approximately 40% at three years (Table 3).^23,24 Benefits became apparent early, after 12 months, and were sustained for at least five years. Risedronate hip fracture data come from the Hip Intervention Program (HIP) study of over 9,000 women.²⁵ This study included two patient groups; the first were women aged 70-79 who had severe osteoporosis (T-scores ≤ -4 or T-scores ≤ -3 with additional risk factors). In this group, there was a reduction in the incidence of hip fracture of approximately 40% by the third year (pooled data from patients receiving 2.5 mg/day and 5 mg/day). However, in the other group enrolled in the HIP study, women over 80 who had risk factors but no proven osteoporosis, there was no statistically significant reduction in hip fractures. This result is surprising and there have been a number of possible explanations. The group tested may simply have been unusually healthy, which suggests that bone mineral density testing is an important predictor of the efficacy of osteoporosis therapy. In addition to the conflicting data from the HIP study, the VERT studies showed no effect on the occurrence of hip fractures. Although hip fracture was not a primary endpoint, the results are remarkable and possibly due to the high dropout rates seen in these studies.


Recombinant parathyroid hormone (PTH)
Parathyroid hormone is a principal regulator of calcium homeostasis and works through a mechanism completely different from that of estrogen, SERMs, calcitonin, or bisphosphonates. PTH is a bone-formation stimulating agent. It not only increases bone mass, but also seems to restore bone architecture by filling in cavities and cancellous bone caused by the bone loss process. PTH can cause large increases in bone mass both when given alone and when combined with antiresorptive agents. Clinical trials are now underway assessing the effectiveness of PTH in combination with bisphosphonates or raloxifene. PTH may receive FDA approval in late 2002 or 2003.

The largest study of PTH included 1,637 women with low BMD and an average of 2.3 fractures at baseline.²⁶ They were randomized to receive either placebo or either 20 or 40 µg/day of PTH. Median follow-up was 21 months. After a median treatment period of 18 months, PTH was shown to have a potent effect on fracture occurrence, with a reduction of 65% to 69% in the incidence of vertebral fractures and a reduction of 35% to 45% in all nonvertebral fractures. This trial reinforced findings from earlier studies, which showed PTH to be a safe and effective therapy for enhancing bone mineral density. Back pain, nausea, and headache were the most common side effects; these occurred infrequently and were dose-dependent. Fewer than 5% had sustained increases in serum calcium above the normal range.

PTH will doubtless prove to be a valuable addition to the armamentarium, as a single agent or in combination with antiresorptive therapy. It is likely that antiresorptive agents will be required to maintain the bone mass and bone architecture benefits induced by PTH. It is possible that the anti-fracture benefits of PTH and antiresorptive therapy will be additive. Animal studies combining PTH with estrogen or a bisphosphonate have had promising results, producing increases in bone mass, connectivity, and strength.

Summary
In summary, clinicians are fortunate today in having a variety of effective antiresorptive therapies that reduce the risk of vertebral fractures. The bisphosphonates also reduce the risk of nonvertebral fractures, including hip fractures. These drugs can dramatically reduce the disability, the quality of life changes, and the mortality associated with osteoporotic fractures. However, much remains to be done in the area of diagnosis. Only one in three women with vertebral fractures has been diagnosed.¹¹ Osteoporosis can be treated at any stage, but for optimal treatment, it is important that we identify women with osteoporosis prior to the occurrence of the first fracture.