OSTEOPOROSIS 0889-8529/98 $8.00 + .OO

THE ROLE OF CALCITONIN IN THE PREVENTION

OF OSTEOPOROSIS Louis V. Avioli, MD, FACE

PHYSIOLOGIC EFFECTS OF CALCITONIN

Calcitonin, a 32 amino acid polypeptide discovered in 1958,’O is secreted by the thyroidal C cells and is rapidly degraded after oral administration by the high concentrations of peptidase in the gastric secretions. Endogenous calcitonin production and secretion are dependent on the circulating level of ionized calcium. Specifically, low levels of calcium decrease calcitonin secretion; high levels of calcium stimulate calcitonin release. Diets consistently low in elemental calcium result in increased parathyroid hormone (PTH) secretion, decreased calcitonin secretion, and the subsequent stimulation of osteoclastic-regulated bone resorption. By comparison, diets high in calcium result in decreased PTH levels, increased calcitonin production, and a resultant decrease in osteoclastic- stimulated bone resorption. Although the relationships between calcitonin secre- tion and its plasma levels and the development and progression of osteoporosis are ill-defined, defects in calcitonin production and blood levels after the meno- pause have been

Osteoclasts possess specific calcitonin-binding receptors and cause the brush borders of the osteoclasts to disappear, resulting in osteoclast movement away from the bone resorption ~urface.~ Calcitonin does not interfere with the recruit- ment of new bone multicellular ~ni t s .4~ The potent suppressive effects of calcito-

Portions of this text are reprinted with permission from the author’s review entitled “Salmon Calcitonin Nasal Spray: An Effective Alternative to Estrogen Therapy in Select Postmenopausal Women” published in Endocrine 5:115-127, 1996.

From the Division of Bone and Mineral Diseases, Washington University School of Medi- cine, St. Louis, Missouri

ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA

VOLUME 27 NUMBER 2 JUNE 1998 411

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nin on osteoclasts are dose-related and occur within 30 minutes of administra- tion. Other direct actions of calcitonin on osteoclasts include marked alterations of the internal structure of isolated osteoclasts, resulting in restricted cytoplasmic motility of the cells, and a reduction in the lifespan and number of osteoclasts. The net effect of these anti-osteoclastic functions is a significant reduction in the bone resorptive activity and a consequent reduction in bone 1 0 ~ s . ~ The possibility that calcitonin might be effective in decreasing bone loss in osteoporosis was proposed as early as 1970.7

CURRENT INDICATIONS AND FORMULATIONS OF CALCITONIN

The principal calcitonins available for use are porcine, human (synthetic), salmon (synthetic), and eel. Of these substances, salmon calcitonin is the most potent5 Porcine calcitonin is less acceptable as a therapeutic agent because of the frequency of side effects53 and the fact that it has relatively weak biologic activities. Eel calcitonin, which differs from salmon calcitonin with three amino acids in positions 26,27, and 29, is very similar in its action to salmon calcitonin and certainly much more active than porcine calcitonin.28 Elcalcitonin, an ana- logue of eel calcitonin developed in Japan, has been used effectively in and Pacific Rim locales as an antiresorptive agent in osteoporotic Increments in distal radial bone density as high as 13.5% after 6 months of therapy have been recorded with 40 Units daily (intramuscular) for 2 months and 40 Units every second day for the following 4 m0nths.5~ Although these studies were essentially uncontrolled, it can be assumed that elcalcitonin has a biologic potency comparable with that of the natural hormone and is much more stable.

Injectable forms of salmon calcitonin were first indicated for use in the treatment of Paget's disease in the United States in 1974. Subsequently, both injectable (1984) and nasal spray (1995) were authorized for use in the treatment of postmenopausal osteoporosis. The injectionable (intramuscular or subcutane- ous) formulations of salmon calcitonin, however, were often associated with a high rate of noncompliance in elderly patients. The recently approved nasal spray formulation has ameliorated the difficulties inherent in the use of paren- teral formulations and is considered a suitable option as an alternative therapy in postmenopausal patients who are not appropriate candidates for estrogen replacement therapy4 Although oral, rectal, and intrapulmonary drug delivery systems for salmon calcitonin are currently being pursued as alternative modes, the clinical utility of these formulations in reversing the bone loss characteristic of osteoporotic populations is not established.", 39

REVIEW OF PROSPECTIVE CLINICAL TRIAL DATA

Injectable Salmon Calcitonin Formulations

Controlled, prospective clinical trials using the intramuscular and subcuta- neous formulations of salmon calcitonin at doses of 50 to 400 IU administered at daily, every-other-day, or twice-a-week intervals have established the efficacy and safety of salmon calcitonin as a potent antiresorptive agent? With the exception of studies performed in oophorectomized individuals,= the majority

THE ROLE OF CALCITONIN IN THE PREVENTION OF OSTEOPOROSIS 413

of patients have been postmenopausal for at least 4 years. The classical response to calcitonin therapy is either a stabilization of bone loss when compared with that in appropriate age-matched placebo-treated controls or significant increases in bone mineral density (BMD) ranging from 7% to 30%.* Maximal increments in vertebral BMD have been observed in osteoporotic patients with increased bone turnover.8

In a double-blind, placebo-controlled clinical study of the analgesic effect of 100 IU of salmon calcitonin administered intramuscularly in osteoporotic pa- tients with vertebral fractures, a significant reduction in pain intensity in addi- tion to that achieved with the use of injested oral analgesic agents was observed in the group receiving calcitonin.2z This beneficial effect was observed from the second day of treatment onward and was associated with early and increased mobility when compared with that in placebo-treated patients. These controlled studies confirmed earlier “open-study” observations that also established calcito- nin as a potent analgesic agent, the latter response attributed to calcitonin- induced increments in circulating P-end~rphin.’~? 44, 48

In studies of injectable salmon calcitonin in osteoporotic patients, therapy has been well-tolerated, with only occasionally reported side effects such as nausea, which occurs in approximately 10% of patients, and flushing, observed in 2% to 5%. Compliance, which can be followed by an assay of urinary biomarkerszO, 23, 33, 45 or by measurements of BMD, is occasionally hindered with the injectable salmon calcitonin formulations, especially in elderly patients and those receiving long-term treatment.26

Nasal Spray Formulation

With the recognition that, biologically, 50 IU of the subcutaneous formula- tions of salmon calcitonin is equivalent to 200 IU of the nasal spray formulation in short-term (30 days) studies: the efficacy and safety of salmon calcitonin nasal spray have been evaluated in a variety of prospective trials in doses of 50, 100, 200, and 400 IU in women with menopausal ages ranging from less than 3 years to 24 years. Administration protocols in these trials have included daily dosing in the majority of studies for 5 to 7 consecutive days per week. Other dosing schedules that have been attempted are alternate daily dosing (i.e., thrice weekly)I3 and daily dosing on an alternate monthly ~chedu1e.I~ Although individual responses to salmon calcitonin therapy vary with the response condi- tioned by the state of bone turnover,3.8 an analysis of patients treated for 2 years with 200 IU per day revealed an 81% reduction in the relative risk of bone loss when compared with a placebo-controlled group receiving 500 mg of elemental calcium per day.32 The most common adverse effect of the nasal spray formula- tion is rhinitis, which may occur in 10% to 12% of patients. As recorded earlier for the injectable forms, placebo-controlled studies have demonstrated an analge- sic effect of nasal spray calcitonin.34

LOWER-DOSE (50 IU AND 100 IU) REGIMENS

Although it has been recorded that doses of 50 IU of salmon calcitonin nasal spray administered daily on 5 consecutive days per week to postmeno-

*References 1, 8, 13, 14, 16, 23-25, 29, 30, 32, and 42.

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pausal women less than 3 years from menopause result in significant increases in lumbar spine BMD after 1 and 3 years of there is usually minimal response to low doses of the nasal spray

Increments in lumbar spine BMD values of 2.5% have been recorded in young postmenopausal women treated with 100 IU per day; however, in that study, values for the total skeleton and distal and proximal forearm were not significantly increased over those in placebo-treated subjects. In another study in which similar doses of nasal spray calcitonin were used, BMD values at the distal radius were increased by 5% (RO.01) after 1 year of continuous therapy with intranasal salmon calcitonin. Although daily doses of 100 IU per day have been proposed as effective therapy, for postmenopausal women, this dose is relatively ineffective in preventing bone loss in the perimenopause.z

HIGHER-DOSE (200 IU) REGIMENS

Overgaard and c o - ~ o r k e r s ~ ~ evaluated changes in BMD at the proximal and distal forearm and lumbar spine in 17 postmenopausal women with established osteoporosis after 1 year of continuous therapy with daily doses of 200 IU. Unlike placebo-treated controls, treated patients did not lose bone in either axial or appendicular skeletal sites.

To further clarify the relationship between outcomes and dose, Overgaard and colleague^^^ conducted a follow-up dosing study evaluating the outcomes in patients with established osteoporosis who received 50 IU (n = 40), 100 IU (n = 43), or 200 IU (n = 41) of salmon calcitonin nasal spray daily for 2 years. Measured sites were the distal forearm and lumbar spine. Statistically significant increases in the double-blind placebo-controlled study were observed in lumbar spine BMD values at each dose compared with the placebo group, although these increments of 1.8% to 4.2% (mean 3%) were greatest for the 200 IU dose. Vertebral bone mass increased in a dose-dependent manner after 1 and 2 years of therapy. Distal forearm BMD decreased in all patients but to a lesser degree in the group receiving 200 IU salmon calcitonin at 2 years. In addition, there was no difference in the incidence of side effects in the calcitonin and placebo treatment

There is reason to believe that calcitonin affects bone ”quality” in a favorable mannet50 Using a regimen of 200 IU of nasal spray calcitonin per day during alternate months for 2 years, Gonnelli and co -w~rke r s~~ were able to demonstrate a significant increase in the calcaneal ”stiffness index” using an Achilles ultra- sound unit. These observations are noteworthy, because other investigators have advocated ultrasound stiffness as a significant predictor of hip fracture indepen- dent of BMD.46

Ellerington and co-w~rkers~~ compared different dosing schedules using 200 IU of intranasal salmon calcitonin4aily dosing and alternate-day dosing three times per week for 2 years in 36 and 37 patients, respectively. The investigators further subdivided patients into groups according to menopausal age within each dosing group. Patients who were 5 years or less from menopause were classified as “early postmenopausal” patients. Those who were more than 5 years from menopause were classified as ”late postmenopause” patients. Late menopause patients (who also had the lowest baseline BMD values) who re- ceived 200 IU of salmon calcitonin daily showed the greatest response to treat- ment, with increments in lumbar spine BMD of 3.1% when compared with patients receiving placebo. Individuals treated thrice weekly with 200 IU of salmon calcitonin had decreases in lumbar spine BMD that were comparable

THE ROLE OF CALCITONIN IN THE PREVENTION OF OSTEOPOROSIS 415

with those observed in patients taking placebo. Once again, therapy with salmon calcitonin nasal spray was well-tolerated by the majority of patients.13

Impact of Salmon Calcitonin on Fracture Rates

In the past, nonrandomized epidemiologic reviews and analyses of pooled data were consistent with the concept that calcitonin decreased fracture rates in patients with established osteoporosis.6 A Mediterranean osteoporosis study that examined the incidence of hip fracture in 5600 women aged 50 years or older from six countries in southern Europe demonstrated that calcitonin, like estrogen replacement therapy, significantly decreased the incidence of hip fracture.I9 In that study, therapy with injectable calcitonin therapy was associated with a 31% decrease in hip fracture. In comparison, a 25% reduction in hip fracture rate was observed in patients undergoing calcium treatment alone and a 45% reduction in those undergoing estrogen replacement therapy.19 In a study in which post- menopausal women with at least one vertebral fracture received injectable calci- tonin, 100 IU for 10 days per month for 2 years, a 60% reduction in new vertebral fractures was noted in comparison with a placebo-treated p~pu la t ion .~~

An analysis of pooled data obtained from 208 postmenopausal women treated with nasal spray calcitonin for 2 years revealed a reduction in the incidence of new fractures by 66% when compared with a placebo Results of a more recent placebo-controlled study of more than 600 patients treated with daily doses of 200 IU of nasal spray calcitonin for 3 years demon- strated a 37% decrease in the risk for new fractures or for the worsening of previous fractures in osteoporotic women.47

Because drugs that decrease fracture rates in osteoporotic patients usually produce relatively large and sustained increments in BMD,'*, 21 the ability of salmon calcitonin to decrease the incidence of skeletal fractures has often been considered inappropriate for the modest degree of increments in BMD often observed with a drug that preferably decreases osteoclastic re~orp t ion .~~ These concerns should be tempered by the following observations: (1) decreases in bone turnover can be as effective as increases in bone mass in preventing f~actures,4~ (2) bone turnover does not decline after menopause in osteoporotic patients with vertebral fractures7I and (3) maximal effects of calcitonin therapy are seen in osteoporotic patients with high bone turnover syndrome~.~, 8, 23

Resistance to Continued Therapy

Although controversy exists regarding the functional importance of antibod- ies that may develop in as many as 39% of women treated with salmon calcito- nin,18 in healthy postmenopausal women, it has been recorded that nasal calcito- nin maintains the same effect on bone regardless of whether antibodies are

SUMMARY

While the results of ongoing studies continue to expand the knowledge base of the primary care physician in the management of postmenopausal osteoporosis, available data must serve as a guide to the clinician in developing an optimal therapeutic regimen suited to the medical and personal needs of the patient.

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Given the enormous public health consequences of postmenopausal osteo- porosis and osteoporotic fractures, the primary care physician is faced with the challenge of not only educating the growing segment of elderly patients regard- ing the ubiquitous and inevitable decline in bone mass but of actively recruiting appropriate patients for antiresorptive therapy based on current epidemiologic statistics. Estrogen replacement therapy is currently considered the primary antiresorptive therapy for osteoporosis, yet many patients are unable or unwill- ing to accept and initiate prescribed therapy. Moreover, noncompliance with such therapy is observed in patients who initiate treatment. Nasal salmon calcitonin should be considered an appropriate alternative in patients with established osteoporosis who cannot, will not, or should not proceed with estrogen replacement therapy.

The safety profile of salmon calcitonin has been demonstrated in clinical trials since the early 1970s when the first injectable formulation was approved for clinical use and has been confirmed in more extensive well-controlled clinical trials? The new nasal spray formulation offers the advantages of easy adminis- tration, an uncomplicated dosing regimen, and a lack of restrictions related to drug administration with food-all factors that may increase the likelihood of improved compliance with long-term therapy. Furthermore, in patients with vertebral crush fractures, the analgesic action of salmon calcitonin may provide additional pharmacotherapeutic benefit. Drug-drug interactions, a common con- cern in elderly patients receiving multiple agents, have not been reported with salmon calcitonin. It seems justifiable to conclude that salmon calcitonin nasal spray provides the physician with an appropriate alternative approach to estro- gen for the treatment of established postmenopausal osteoporotic syndromes.

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THE ROLE OF CALCITONIN IN THE PREVENTION OF OSTEOPOROSIS 417

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Division of Bone and Mineral Diseases Washington University School of Medicine

216 South Kingshighway Blvd. St. Louis, MO 63110