(Laurie Barclay, MD, July 2003)

Osteoporosis is a disease characterized by low bone mass and structural deterioration of bone, causing increased likelihood of fractures, particularly of the hip, spine, and wrist. In the U.S., approximately 10 million adults have osteoporosis, including eight million women and two million men, and an additional 34 million more, or at least half of individuals over 50 years of age, are at increased risk because of low bone mass.

During their lifetime, half of women and one-quarter of men over age 50 will have at least one osteoporotic fracture. Of more than 1.5 million fractures caused by osteoporosis each year, 300,000 involve the hip, 700,000 the vertebrae, and 250,000 the wrist. In 2001, direct hospital and nursing home costs related to osteoporosis and associated fractures were $17 billion, or $47 million daily.

Bone loss typically occurs without symptoms before the fracture becomes evident. In the case of vertebral collapse, there may be severe back pain, kyphosis, or loss of height. Bone density testing can detect osteoporosis before a fracture occurs, determine rate of bone loss, and monitor treatment response.

Risk factors for osteoporosis include history of fracture after age 50 or in a first-degree relative, low bone mass, female gender, thin stature with small frame, advanced age, family history of osteoporosis, estrogen deficiency related to menopause, amenorrhea, anorexia nervosa, and low testosterone levels in men. Chronically low dietary calcium intake, use of corticosteroids or anticonvulsants, smoking, sedentary lifestyle, and excessive alcohol use also increase risk.

Medications currently approved by the Food and Drug Administration (FDA) to prevent and/or treat osteoporosis in postmenopausal women include the bisphosphonates such as alendronate (Fosamax) and risedronate (Actonel); calcitonin; estrogen and hormone therapy preparations; parathyroid hormone such as teriparatide (Forteo); and selective estrogen receptor modulators (SERMs) such as raloxifene (Evista).

Compliance is definitely an issue for osteoporosis treatment and prevention, especially when the drug must be taken daily or when adverse events seem worse than the consequences of a relatively asymptomatic condition.

CenterWatch has identified a pipeline of 19 drugs in various stages of development for osteoporosis. Most of them act via hormonal or metabolic pathways affecting bone turnover, and some can be administered once weekly or even less frequently in hopes of improving compliance.

On May 19, Roche Holding AG said that U.S. regulators had approved a once-daily formulation of Boniva (Bonviva; ibandronate) for treatment and prevention of osteoporosis in postmenopausal women. Like other bisphosphonates, Bonviva inhibits bone turnover by decreasing bone resorption. Approval was based on data showing reduced incidence of new vertebral fractures.

In conjunction with GlaxoSmithKline, Roche is developing an improved version of ibandronate that does not have to be administered daily, making it more competitive with Fosamax, which is only given once weekly. Trials are underway with administration of ibandronate once every three or four weeks. Ibandronate is also marketed in Europe under the trade name Bondronat for bone complications of cancer.

Another biphosphonate given once weekly is a new formulation of risedronate, in phase III testing in Japan by Takeda Pharmaceuticals.

Novartis' answer to the problem of poor compliance with daily or even weekly regimens is Zometa (ZOL446; zoledronic acid), a bisphosphonate osteoclast inhibitor now in phase III development.

In a study published last year in the New England Journal of Medicine, 351 postmenopausal women with low bone mineral density (BMD) were randomized to receive placebo or different intravenous dosages of Zometa at three, six, or 12 month intervals. Compared with the placebo group, women treated with Zometa had increases in BMD ranging from 4.3% to 5.1% at the spine and from 3.1% to 3.5% at the femoral neck, regardless of frequency of administration.

The investigators commented that these increases in BMD were similar to the effects of daily regimens of bisphosphonates such as Fosamax. The most commonly reported adverse effects were musculoskeletal pain, nausea, and fever.

Zometa is currently FDA-approved for bone metastases, and if efficacy is confirmed in large clinical trials, Novartis may file for FDA approval for osteoporosis in 2005.

On March 6, Unigene Laboratories Inc. filed a new drug application (NDA) with the Food and Drug Administration for Fortical. This nasal formulation of recombinant salmon nasal calcitonin inhibits bone resorption. The FDA accepted the NDA for review on May 5, triggering a $3 million milestone payment from Upsher-Smith Laboratories, Unigene's exclusive U.S. licensing partner.

Unigene has also submitted an NDA for Forcaltonin, an injectable calcitonin which is approved in Europe for the treatment of Paget's disease and hypercalcemia associated with malignancy.

Unlike the biphosphonates and calcitonin, which inhibit bone loss due to resorption, parathyroid hormone (PTH) speeds up both bone formation and resorption with a resulting net increase in bone formation. PREOS (ALX1-11) is a recombinant version of human PTH in phase III development by NPS Pharmaceuticals.

In a phase II trial of over 200 postmenopausal women, daily injections of PREOS (100 micrograms) increased mean BMD by nearly 8% over one year of treatment. Ongoing phase III trials include the Treatment of Osteoporosis with PTH (TOP), an 18-month, double-blind, placebo-controlled, multicenter trial testing the efficacy of PREOS in reducing fractures in postmenopausal women who are not receiving drug or hormone therapy for osteoporosis.

In Europe, the PTH for Osteoporotic Women on Estrogen Replacement (POWER) study is testing the effect of daily subcutaneous injections of PREOS or placebo for 24 months in addition to ongoing hormone replacement therapy.

Because PREOS works differently than does Fosamax, Novartis is comparing both drugs individually and in combination in the PTH and alendronate, or PaTH, Study coordinated by the University of California, San Francisco, and sponsored by the National Institutes of Health.

This 24-month, randomized, double-blind trial at four U.S. centers will enroll 240 postmenopausal women aged 55 to 85 years. The primary outcome measure is BMD, with secondary outcomes including fractures, biochemical markers of bone metabolism, and effects on quantitative computed tomography scans of the hip and spine and ultrasound scans of the heel.

Lasofoxifene, an estrogen mixed agonist/antagonist that binds selectively to the human estrogen receptor-alpha, is in phase III testing by Pfizer. This SERM decreases bone loss and has favorable effects on blood cholesterol, and laboratory studies suggest that it may also prevent the growth of certain breast cancer cells.

From October 2001 to March 2006, the Postmenopausal Evaluation And Risk-reduction with Lasofoxifene (PEARL) study will assess safety and efficacy in reducing the risk of osteoporotic fractures. Secondary outcomes will also include incidence of primary breast cancers, coronary events and hospitalizations for cerebrovascular disease. This randomized, double-blind, placebo-controlled, worldwide trial will enroll 7,500 women.

Also in phase III development is the Wyeth SERM TSE-424, a combination of bazedoxifene and conjugated estrogens. Ongoing trials are comparing this drug to placebo and to raloxifene for the treatment of osteoporosis in postmenopausal women.

Additional drugs targeting estrogen pathways include Apomine (SR 45023A), a bisphosphonate estrogen derivative in phase I/II testing by ILEX Oncology, and trimegestone (a 19-norpregnane derivative) combined with 17-beta estradiol, in phase III development by Wyeth Research.

Using nitric oxide (NO)-releasing derivatives of non-steroidal anti-inflammatory drugs (NSAIDs), NicOx SA is testing an innovative approach to osteoporosis which has already proved applicable to the the treatment of pain and rheumatoid inflammatory disorders. Their phase II product HCT 1026 is an NO-releasing derivative of the NSAID flurbiprofen.

Preclinical testing in animal models suggested that HCT-1026 is a potent inhibitor of bone resorption. Phase I clinical trials in the UK have shown that HCT-1026 is tolerated as well as conventional NSAIDs. Compared with existing drug therapies for osteoporosis, inflammatory joint disease and Paget’s disease, HCT-1026 is expected to significantly reduce adverse effects. This versatile compound may also have applications to the treatment of urge urinary incontinence and dermatological disorders.

In a disease such as osteoporosis, marked by few symptoms until irreversible complications develop, compliance with prevention regimens is often difficult to enforce. Development of new drugs in the pipeline must therefore focus on tolerability and ease of administration as well as safety and efficacy. The complex interactions of various hormones influencing bone resoprtion and formation provide multiple therapeutic targets that will hopefully lead to effective new drug therapies promoting compliance.