Osteoporosis Therapies
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Osteoporosis: Therapies

researched and written by the ProjectAWARE group, 2001

Current Therapies New & Experimental Therapies
  Estrogen & HRT   Hip protection pads
  Bisphosphonates   Growth hormone
  Calcitonin   Parathyroid hormone
  SERMs   Progesterone
  Injection of bone cement   Tibolone & others
      Thiazide
      Sodium fluoride
       

The optimal goal for the treatment of osteoporosis, especially for patients who already have advanced bone loss, is to increase bone mass and bone strength to levels seen in average young women and men so as to prevent all osteoporotic fractures. Indeed, with the rapid aging of the population, there is an urgent need for a cure, not merely the management of osteoporosis. This goal is not attainable with present pharmacotherapies.5

The pharmacotherapies currently approved by the Food and Drug Administration for the treatment of osteoporosis—estrogen, raloxifene, alendronate, risedronate and calcitonin—are antiresorptive agents that work by slowing the rate of bone remodeling. Thereby, they slow or retard bone loss. None of these agents is capable of rebuilding bone. The small but variable increases in bone mineral density (BMD) in patients treated with antiresorptive agents are not due to bone rebuilding. Instead, they are the result of contraction of the remodeling space and more complete secondary mineralization.5

During and following menopause, estrogen administration (ERT) is important, not only in slowing bone loss, but also significantly decreasing hip and vertebral fractures. However, neither estrogen nor increased bone density is likely to reduce fracture risk once there is substantial trabecular bone loss.9, 13, 38

Observational studies have indicated a significant hip fracture reduction in women who maintain hormone replacement therapy (HRT); still trials with fractures as the endpoint are scarce. HRT trials have shown decreased risk of vertebral fractures, but there have been no trials of estrogen with hip fracture as the primary outcome.33

Trials have shown that physical activity is necessary for bone building and maintenance through adulthood. Complete bed rest and microgravity have devastating effects on bone. Exercise intervention has had the most effect during skeletal growth and in very inactive adults. Improved muscular strength and balance may be very significant in fracture-risk reduction, and trials in older adults have successfully used various forms of exercise to reduce falls. High-impact exercise (weight training) stimulates accrual of bone mineral content in the skeleton. Lower impact exercises, such as walking, have beneficial effects on other aspects of health and function, although their effects on bone density have been minimal.33

There is an urgent need for randomized clinical trials of combination therapy, which includes pharmacologic, dietary supplement, and lifestyle interventions (including muscle strengthening, balance, and management of multiple drug use, smoking cessation, psychological counseling, and dietary interventions).33

Current Therapies

Estrogen and HRT

Estrogen replacement therapy (ERT) can improve bone density measurements in osteoporotic women20, but does not eliminate risk of fractures. It was originally thought that estrogens only restrain the osteoclasts. Now we know that estrone stimulates the development of the osteoblasts (as well as myoblasts, which form muscle tissue).14 However, once estrogen administration ceases, the rate of bone mineral density decline returns to that of untreated women during the immediate postmenopausal period.10

The effective dose of conjugated estrogens has been found to be as low as 0.3 mg/day.11 However, most studies have found a dose of 0.625 mg to be more widely effective. Other forms of oral estrogen seem to be equally efficacious and, because the action is directly upon the target tissue, route of administration does not seem to matter.21

Treatment intervals, routes of administration, and dosages have varied among the many favorably reported studies. On average, it takes from 5-10 years of ERT before a significant difference in fracture incidence can be demonstrated.10

An improvement in bone density can be demonstrated after as short a therapy interval as 6 months.11 However, to be effective in controlling osteoporosis, ERT must be taken for at least 15 years from the last menses until roughly the age of 70 or longer.33

Hormone replacement therapy (HRT) is an established approach for osteoporosis treatment and prevention. Many short-term studies and some longer term studies with bone density as the primary outcome have shown significant efficacy.33

Data demonstrating the beneficial effect of hormone replacement for women with osteoporosis is strong. Results from the WHI (Women's Health Initiative) have validated smaller studies that demonstrated fracture reduction for patients taking replacement therapy. In addition, the association between HRT and breast cancer is clear and must be carefully considered, especially in high-risk patients.12

While combined hormone replacement therapy (HRT) offers "undeniable and significant reduction in osteoporosis, the synthetic progesterone (progestin) used in HRT carries with it another set of risks." 23 Micronized progesterone is the preferred progestogen until new information points to another choice.12 Diet, exercise, and lifestyle factors offer identical benefits without the risks.23

Young women with osteopenia should not be frightened, but should be concerned enough to discuss estrogen with their physician so that they do not develop osteoporosis in the future. Elderly women with osteopenia are above average for their age and don't require more than activity and a good calcium intake (although even in the elderly estrogen will make the bones even stronger and will have other benefits).6

Unfortunately, hormone replacement is often not quite as simple as just replacing one hormone, as is sometimes implied by proponents. Nor is bone density a simple matter of hormone replacement.47

The real difficulty is to find the desirable levels of the hormones estrogen, progesterone and testosterone required, and this can to some extent be gauged by doing serial salivary hormone levels when using hormone replacements, taking into account the levels of the three hormones as well as their relative levels. Many practitioners have found that by adequately restoring and balancing these three hormone levels, bone densities do increase significantly over a period of two years, during which time overall well-being also increases.47

Bisphosphonates

Randomized placebo-controlled trials of cyclic etidronate, alendronate, and risedronate analyzed by a systematic review and meta-analysis have revealed that all of these bisphosphonates increase bone density at the spine and hip in a dose-dependent manner. They consistently reduce the risk of vertebral fractures by 30 to 50 percent. Alendronate and risedronate reduce the risk of subsequent nonvertebral fractures in women with osteoporosis and adults with glucocorticoid-induced osteoporosis. There is uncertainty about the effect of antiresorptive therapy in reducing nonvertebral fracture in women without osteoporosis.33

With bisphosphonates, there is a one-time increase in the bone density (it's like cashing in your life savings all at once). As with estrogen, if the bisphosphonate medication is stopped, bone density will decrease again. If it is not stopped, bone density reaches a plateau. The bisphosphonates get deposited in the bone and will accumulate for years. Maybe they will continue to prevent bone loss for 30 years without loss of bone strength. We don't have any data longer than 5 years for alendronate. It is possible that many years of accumulated medicine would weaken the ability of the bone to repair damage.6

Etidronate (Didronel), in doses that are now considered too high, was first used over 20 years ago to treat patients with osteoporosis. They developed osteomalacia (calcium deficiency in bone). These results discouraged studies until a decade later, when investigators began to focus on cyclical regimens for treatment of osteoporosis.6

Alendronate (Fosamax), a second generation bisphosphonate, is 1,000 times as potent as etidronate in blocking bone resorption. It is deposited in the bone and has a very long half-life (greater than 10 years). Several studies have convincingly showed improvement in bone density at the spine and the hip after 2 to 4 years of treatment. Most of the increase happens in the first year. The effective dose for increasing bone density has been found to be 5 or 10 mg/day, however, new evidence shows 35mg once a week is effective. The Fracture Intervention Trial (FIT) documented significant fracture reduction at 2 years with the 5mg/day dose.6

Risedronate (Actonel) was recently approved for treatment of osteoporosis. The results appear similar to alendronate. Risedronate significantly reduces the risk of hip fracture among elderly women with confirmed osteoporosis but not among elderly women selected primarily on the basis of risk factors other than low bone mineral density.26 There are conflicting data about whether more gastrointestinal side effects are seen with alendronate than with risedronate. At this time, this newer bisphosphonate does not seem to provide any definite advantage to alendronate for the treatment of osteoporosis, other than possibly price.6

One researcher puts it this way: "Risedronate prevents fractures - sometimes." In a large hip-fracture endpoint trial, the rate of hip fractures was reduced in postmenopausal women younger than 80 who had established osteoporosis or who were at very high risk. In women older than 80, however, who did not have bone density measurements, there was no reduction in rate of hip fracture. The reasons are not yet clear, but it could be due to the more overwhelming impact of falls.6

Estrogen improves the bone density better than new drugs such as alendronate (Fosamax) and calcitonin (Miacalcin). The long-term safety of alendronate is unknown, so it is not wise to use it for prevention unless there are other strong risk factors. In fact, the recent large FIT study showed that in those with osteopenia, the percentage of women who developed new fractures after 4.5 years was 10% in women taking placebo and 11% in women taking alendronate. The trabecular bone becomes more brittle, and is thus more prone to fracture, as the bone replacement is non-organic and cannot grow.6

There is no evidence that using a combination of estrogen and bisphosphonates helps to prevent osteoporotic fractures, but it does add to the expense and potential toxicity. Another option for the 50-70 year old woman with osteopenia who can't take estrogen due to breast cancer is to wait a few years (just use calcium and exercise) until there is more information about the new estrogen-like medications that may suppress breast cancer.6

Calcitonin

Calcitonin is a naturally occurring hormone that acts directly on osteoclasts (via receptors on the cell surface for calcitonin), and bone biopsies from patients treated with the drug show no effects on mineralization. It has a short half-life. In one study, calcitonin given as a subcutaneous injection showed significant improvements in bone density, however, there was a high incidence of side effects, including pain at the injection site, flushing and nausea, which limited the use of the drug.6

Calcitonin is now available as a nasal spray, which has made it much more tolerable for patients. The studies using this drug have not included as many subjects as the studies of bisphosphonates, but available data does show increases in bone density. However, the increases are not as great as with the bisphosphonates, and the bone formation rate is not as depressed. This natural hormone has been in clinical use for many years with a good safety profile. Minor adverse effects such as nasal irritation are seen in a small number of patients. Calcitonin does not reduce the serum calcium levels below normal in patients with postmenopausal osteoporosis but has been shown to reduce magnesium levels in some cases.6

Salmon calcitonin has demonstrated positive effects on bone density at the lumbar spine, but this effect is less clear at the hip. Other than a recently completed randomized controlled trial of nasal calcitonin, no analysis of fracture risk is available. The PROOF study revealed a significant reduction in vertebral fracture risk at a 200 IU dose but not at a 100 IU or 400 IU dose. The absence of dose response, a 60 percent dropout rate, and the lack of strong supporting data from bone density and markers decrease confidence in the fracture risk data from this trial.33

Calcitonin is a safe alternative to estrogen in women who cannot or will not take estrogen. There are no data about effectiveness of adding calcitonin to estrogen.6

SERMs (Selective Estrogen Receptor Modulators)

Estrogen has effects on many different tissues. These effects are mediated by intracellular estrogen receptors. The estrogen receptors are complex, and after binding with estrogen the receptor changes configuration. These conformational changes are different in different tissues, and analogs of estrogen can inhibit the final estrogen effect in some tissue but not others.6

In postmenopausal women, estrogen improves bone mass and serum lipid concentrations, effects that are beneficial. Estrogen also causes endometrial hypertrophy and vaginal bleeding, which are undesirable side effects, and it stimulates breast tissue, which may account for the increase in breast cancer seen after long-term use.6

The development of selective estrogen receptor modulators (SERMs) has been an important new thrust in osteoporosis research. The goal of these agents is to maximize the beneficial effect of estrogen on bone and to minimize or antagonize the deleterious effects on the breast and endometrium. Tamoxifen, used in the treatment and prevention of breast cancer, can maintain bone mass in postmenopausal women, however, effects on fracture are unclear. Raloxifene, a SERM approved by the FDA for the treatment and prevention of osteoporosis, has been shown to reduce the risks of vertebral fracture by 36 percent in large clinical trials.33

Tamoxifen, the first available SERM, was used as adjunct therapy in women with breast cancer; however, tamoxifen's protective effect on breast cancer appears to wear off after five years. Increased bone density was noted in these women. Tamoxifen also stimulates the endometrium. In women with an intact uterus, progesterone therapy would be needed to protect against endometrial carcinoma, but the progesterone has been found to stimulate breast tissue which could lead to recurrence of cancer.6

Raloxifene (Evista) has recently been approved for prevention of osteoporosis. This SERM has protective effects on the breast, and it decreases the LDL cholesterol (although it does not increase the HDL cholesterol). There is no stimulation of the endometrium. Bone density shows small increases, which are less than seen with estrogen. Raloxifene potentially could be useful in prevention of osteoporosis, but the skeletal effects do not appear to be strong enough to use it as a first choice in treatment of established disease.6

Injection of polymethylmethacrylate bone cement (vertebroplasty and kyphoplasty)

Due to the challenges of reconstruction of osteoporotic bone, open surgical management is reserved only for those rare cases that involve neurologic deficits or an unstable spine. Recently, there has been increased interest in two "minimally invasive" procedures for management of acute vertebral fractures, vertebroplasty and kyphoplasty, which involve the injection of polymethylmethacrylate bone cement into the fractured vertebra.

Anecdotal reports with both techniques claim frequent acute pain relief; however, neither technique has been subjected to a controlled trial to demonstrate the benefits over traditional medical management. Furthermore, the long-term effect of one or more reinforced rigid vertebrae on the risk of fracture of adjacent vertebrae is unknown for both of these procedures.33

 

New and Experimental Therapies

Hip protection pads

Nonpharmacologic interventions directed at preventing falls and reducing their effect on fractures have been promising. These include studies to improve strength and balance in the elderly, as well as using hip protectors to absorb or deflect the impact of a fall.33

A large new study published in the New England Journal of Medicine has shown that hip protectors prevent falls.17 This study was community-based and involved 1801 frail elderly patients. Those assigned to the hip protector group had half as many fractures. Of 1034 falls, only 4 hip fractures occurred while patients were wearing the protectors. The brand of the hip protector used in this study was KPH Hip Protector, from Helsinki, Finland.6

Hip protection pads prevent osteoporotic hip fracture in elderly women as long as they are wearing the pads and are now available in the US under the brand name "SafeHip".6

Growth Hormone

Growth hormone has been studied as a method of increasing bone density in elderly persons. The results are mixed. Biochemical markers of bone formation and resorption increase, and in some cases bone density increases modestly. Side effects are seen, however, which limit potential use.6

Patients with adult-onset pituitary deficiency may have osteoporosis. These patients also have hypogonadism, which is known to decrease bone density. In these cases growth hormone may improve bone density beyond that seen with sex hormone replacement. Adults who had childhood onset growth hormone deficiency do not necessarily have osteoporosis. They have short stature, but the volumetric density of the bone is normal. Thus, the physiological role of growth hormone in maintaining adult bone density is uncertain.6

Parathyroid Hormone

Parathyroid hormone (PTH) looks promising as a treatment for osteoporosis. PTH peptides are the most promising of the anabolic agents, but are still in clinical trials33. Several studies have been done which show substantial increases in spinal bone density with PTH injections. The bone density of the hip also increases, and data shows reduction in fracture rates. These studies which show benefit were all done in combination with estrogen, which seems to protect the cortical bone from the ill effects of PTH, although there might still be a little increase in the cortical porosity.6

The role of PTH in control of bone mass is perplexing. PTH stimulates osteoblastic activity, especially on trabecular surfaces. In some cases this effect predominates over the increased resorption, and osteosclerosis results. Patients with either primary or secondary hyperparathyroidism have increased bone density of the spine, but decreased cortical bone mass. Iliac crest bone biopsies show increased trabecular bone volume but cortical thickening. Patients with osteoporosis treated with PTH show increases at the spine but decreases at cortical sites. Recent studies using a combination of PTH and estrogen in postmenopausal women have shown increased bone density at both the spine and the hip.6

Whether PTH will be used as direct therapy, or whether one of the cytokines released by PTH-stimulated stromal cells or preosteoblasts will emerge as the treatment of choice, is unknown. For now, the antiresorptive agents continue to be the mainstay of drug therapy for osteoporosis.12

There is a critical need to develop and assess anabolic agents that stimulate bone formation.33

Progesterone

   


Clarification:
The terms "progesterone" and "progestin" are often used interchangeably. Many medical practitioners and scientists do not differentiate between progesterone and progestin, both of which fall into the category of progestogens. However, there are differences both in chemical structure and effect. For clarity and accuracy, ProjectAWARE feels it’s important to distinguish these differences. Therefore, throughout this site, "progesterone" means the endogenous hormone produced in the ovaries; "natural progesterone" refers to bio-identical hormone products known as micronized progesterone or natural micronized progesterone; and "progestin" refers to any of the synthetic progestogens with altered chemical structures that have progesterone-like actions in the uterus.

     

Experimental, epidemiological, and clinical data has indicated progesterone is active in bone metabolism. Critical analysis of the reviewed data indicate that progesterone meets the necessary criteria to play a causal role in mineral metabolism. This review provides the preliminary basis for further molecular, genetic, experimental, and clinical investigation of the role(s) of progesterone in bone remodeling.37

Despite the fact that many articles and even some books advocate progestin as an alternate to estrogen for building bone, several studies have concluded that progestin does not result in any additional benefits to the bone in women who are taking estrogen, either premenopausal36, 16, 1 or postmenopausal 25, 6

The only currently accepted/proven reason to take progestins is to protect the uterus from cancer. The form commonly given in the USA is a progestin called medroxyprogesterone (Provera), which can be given in cyclical or daily doses. Both cyclical and daily dosing have been shown to result in a risk of endometrial cancer that is lower than in women taking "unopposed" estrogen, although after many years there may still be a slight risk. Another form has been approved, micronized progesterone (Prometrium) also called natural progesterone. This comes in 100 mg tablets, and can be used cyclically at 200mg/day for 12 days a month or 100 mg/day daily. It may also be compounded by compounding pharmacies as an oral capsule or transdermal application.6

In one random clinical trial, progestin did cause increased bone density at some skeletal sites in comparison to placebo, but it did not add to estrogen therapy and was definitely not as beneficial as estrogen. In young women taking injectable medroxyprogesterone acetate (Depo-provera)* for contraception, the bone density is lower than in control women. This is a situation where the high progestin clearly is NOT beneficial. It has been shown that Depo-provera is associated with lower bone density, especially in young women.6

* Medroxyprogesterone acetate (Depo-provera) is a progestin (synthetic progestogen), not natural progesterone.

New information suggests that progestins may increase the risk of breast cancer and may make the breast tissue denser. Given these facts, it is not clear what to recommend, and there are few studies on natural progesterone. Certainly breast cancer is much worse than endometrial cancer. A hysterectomy almost always cures endometrial cancer. Some physicians have recommended progestins for 2 weeks every 6 months, which causes withdrawal bleeding and no problems in a small study of 150 women. Willett (JAMA, 2000; 283:534) says "This approach seems logical, but direct evidence is lacking." 6

In postmenopausal women initiating hormone replacement therapy (HRT), dydrogesterone (a progestin) does not contribute to the beneficial effects of HRT on the skeleton, and in fact it may reduce the beneficial effects of estrogen on bone resorption.43

The findings, which contradict some previous research, come from a UK study led by Dr. Jonathan H. Tobias of the Bristol Royal Infirmary in the UK. In a double-blind protocol, his team randomized 26 women to receive 2 mg estradiol daily or 2 mg estradiol plus 10 mg dydrogesterone daily for 8 weeks.43

When given alone, estrogen appeared to be associated with significantly higher osteocalcin levels (a marker of bone formation) and significantly reduced urinary deoxypyridinoline excretion (a marker of bone resorption) compared with combination therapy, the researchers report in the March issue of the Journal of Clinical Endocrinology and Metabolism.43

Tibolone, and Conjugated estrogens and Norgestrel

Doctor's Guide reviews the outcome of a recent study as reported in Menopause 2000;7:327–333

"Two Regimens May Prevent Osteoporosis: Tibolone as well as conjugated oestrogens, plus sequential Norgestrel significantly increase bone mineral density and should prevent osteoporosis in postmenopausal women, a new study confirms."

During the study, 50 women volunteered not to receive treatment, 32 women received tibolone and 31 received conjugated estrogens plus sequential norgestrel. The authors measured bone mineral density at baseline as well as after 48 and 96 weeks using dual photon absorptiometry. After 96 weeks, women who received either tibolone or conjugated estrogens plus sequential norgestrel showed increased bone mineral density at all sites. The control group showed reduced bone mineral density compared to baseline.

The authors concluded that both tibolone and conjugated estrogens plus sequential norgestrel significantly increase bone mineral density in postmenopausal women. On the other hand, bone mineral density declines in postmenopausal women who opt not to be treated. The findings confirm that both tibolone and conjugated estrogens plus sequential norgestrel should prevent osteoporosis.48

Thiazide

Several large, prospective epidemiological studies in elderly men and women have shown that thiazide use is associated with a reduced risk of hip fracture. Several possible mechanisms could explain this association. Thiazides act directly on the distal nephron to enhance calcium reabsorption. In men with hypercalciuria, thiazides lower urine calcium and lead to positive calcium balance. Thiazides may also reduce osteoclastic activity, possibly by inhibiting carbonic anhydrase.6

One randomized study of treatment of systolic hypertension included bone mass as a secondary endpoint in a subset of patients. The subjects who took thiazide had increased bone mass, whereas those on other forms of antihypertensive medication showed decreases in bone mass. The effect of thiazides on bone density in patients with normal blood pressure has not been studied, but a randomized trial is underway.6

Sodium Fluoride

From the 1950s through the 1980s, sodium fluoride, an anabolic agent, was widely advocated as a treatment that reduced fractures and improved radiographic defects. One of the strongest proponents of this therapy was the Mayo Clinic in Rochester, Minnesota. In the 1980s, the National Institutes of Health funded 2 prospective, controlled trials of fluoride therapy in postmenopausal women. Trials were conducted at the Mayo Clinic and the Henry Ford Hospital in Detroit.12

In these studies, fluoride treatment was found to increase bone density values but did not reduce the rate of fractures. On the contrary, the treated subjects experienced more fractures, especially in the lower extremities, than the placebo groups. The increased bone density values were explained by the fact that the substitution of fluoride in the hydroxyapatite crystal produces a denser crystal called fluoroapatite. The surprising results from these trials rang a death knell for fluoride therapy in the United States, at least for daily doses of 75 mg or more.12

Another study found that fluoride definitely increased the bone formation rate as well as the bone density, however, osteomalacia still resulted. In a large well-designed randomized, blinded clinical trial, women who used fluoride for four years had increased fracture rates compared to placebo controls. The bone density of the spine increased by 32%, but the hip did not show increased density and the rate of hip fractures was nearly three times as high in the fluoride group. After this study was published, investigators wondered if even lower doses of fluoride might reduce fracture risk. A relatively small study of low-dose, slow-release fluoride has suggested a reduction in fracture risk, but many of the subjects had not taken the fluoride for more than two years. There was no osteomalacia seen in those subjects who had bone biopsies. However, another group measured the mechanical strength of bone in patients receiving low dose fluoride for five years, and found it was significantly more fragile than bone from control patients.6

At this time fluoride cannot be recommended for clinical use, but because it is one of the few medications that can enhance osteoblast activity, it deserves further research.6

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Risk Factors for Osteoporosis & Fracture
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