Post menopausal osteoporosis is by far the most common form of osteoporosis. Various therapies have been approved in the United States, including the administration of oral estrogen, sodium fluoride, and, on an experimental basis, intranasal calcitonin. However, the widespread use of these agents has been limited by various factors, including expense, safety and lack of proved efficacy. A search continues in the art for an inexpensive, safe and effective treatment for osteoporosis.
Organic bisphosphonate compounds have been found to inhibit bone resorption which is mediated by osteoclasts. The earliest publication describing the administration of diphosphonates for treatment of osteoporosis was in 1979 when Frost described the "Treatment of osteoporosis by manipulation of coherent bone cell populations." Frost continued a series of publications (Frost, "The ADFR Concept and Monitoring It:" in Bone Histomorphometry 1980, 317-321; Frost, "The Evolution of Osteoporosis Therapy" in Orthopedic Clinics of North America, 12, 603-610, 1981; Frost, "Coherence Treatment of Osteoporosis," Orthopedic Clinics of North America, Vol. 12, 649-669, 1981; and others). This coherence concept has been modified by several other authors. In principle, it consists of a stimulation of bone turnover with phosphorus or parathyroid hormone, followed by blocking the resorption with intermittent therapy of blocking agents such as calcitonin or diphosphonates. This therapy, although theoretically very attractive, did not find widespread application because of the difficulty in determining a correct dose for an individual patient and the correct period of time required for stimulation and suppression of individual bone remodelling sites (without exerting an effect on formation). It appears that somewhere between three days and three weeks, most resorption sites should be suppressed. However, no exact information is available anywhere to unequivocally prove this hypothesis.
Since the work by Frost in 1979, many have conceived of different treatment regimens using different compounds and modes of administration. U.S. Pat. No. 4,761,406 to Flora et. al. represents one such example, and is an example of the well-known coherence therapy (except that the stimulation step is apparently omitted, with no apparent advantage to omitting that step). Flora '406 discloses and claims a treatment regimen which employs compounds (polyphosphonates) known in the prior art for treatment of osteoporosis. According to the regimen disclosed in U.S. Pat. No. 4,761,406, at least two cycles are performed, each cycle comprising a daily administration period, during which the polyphosphonate is administered every day, and a rest period.
The bisphosphonate etidronate has been used in animal and clinical trials in the treatment of osteoporosis in various regimes, including continuous therapy, in intermittent cyclic therapy or DFR (Depress, Free, Repeat), or in combination with other agents in an intermittent cyclic therapy known as ADFR (Activate, Depress, Free, Repeat) (see the Frost references mentioned above).
U.S. Pat. Nos. 4,812,304, 4,812,311 and 4,822,609 disclose the use of ethene-1-hydroxy-1, 1-diphosphonic acid or salts or esters thereof in the ADFR treatment. The treatment comprises one or more cycles, wherein each cycle includes a bone activating period of 1 to 5 days during which a bone activating amount of a bone cell activating compound is administered daily. That step is followed by a bone resorption inhibition period of about 10 to 20 days, during which ethane-1-hydroxy-1,1-diphosphonic acid or salt or ester thereof is administered daily in a relatively low amount, followed by a rest period of 30 to 180 days, during which the patient receives neither a bone cell activating compound nor a bone resorption inhibiting polyphosphonate. Other bone resorption inhibiting polyphosphonates are disclosed but not claimed in these patents.
U.S. Pat. No. 4,761,406 discloses basically the same process as described in the patents mentioned in the above paragraph, except that the bone cell activating compound administration step is eliminated. Thus, a treatment regime is suggested involving administering a bone resorption inhibiting polyphosphonate on a daily basis and in a limited amount, followed by a rest period of about 50 to 120 days, with such a treatment regime being repeated at least twice. The patent claims an increase in bone mass results, which is also a result disclosed in U.S. Pat. Nos. 4,812,304, 4,812,311 and 4,822,609.
Treatment for osteoporosis typically requires extended, sometimes chronic, treatment, and patient compliance is a major problem. Those who suffer from osteoporosis would benefit significantly from a new treatment regime which is effective, is easy to administer and/or requires fewer administrations, and avoids or minimizes side effects such as gastrointestinal problems (e.g., as caused by bisphosphonates such as clodronate and pamidronate, when administered orally). Such persons would also benefit from a new treatment regime which can be administered by a wider variety of modes.
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USPTO Backgrounds