Alendronate: Helping Bones Get Stronger

Osteoporosis, Paget’s Disease and Alendronate

Alendronate-CAS-66376-36-1As part of the of drug family called bisphosphonates alendronate sodium works by increasing the thickness of bone by slowing down the cells that usually break down bone. This allows the cells that build bone to work more efficiently. Alendronate can help to reduce the incidence of osteoporosis-related fractures by making bones stronger.

Most patients can expect to see an increase in bone density after 3 months. Alendronate can help treat and prevent osteoporosis as long as it is taken consistently. Alendronate controls but does not cure osteoporosis and Paget’s disease of bone, but instead slows down the progression of these conditions.

Short-term use of Alendronate

In results from the Fracture Intervention Trial Long-term Extension (FLEX) study published in 2006 suggests that some women can eventually stop or take a break from taking Alendronate. That study included women who had taken Alendronate for at least five years. The participants were randomly assigned to continue the drug or switch to a placebo for five more years. Individuals who discontinued use showed a slow decline in bone density and a moderate increase in the risk for spine fractures. The rate of hip fracture, a far more serious injury, was the same in the both groups. Therefore, Alendronate treatment significantly reduced the incidence of injury and hospitalizations. Read Article

Increased Bone Mineral Density in Denosumab Data Presented at ENDO 2015

ENDO wrist denosumabExciting news was presented at ENDO 2015 regarding the use of Denosumab for osteoporosis in post-menopausal women who are at high risk for bone fractures. Results from a comprehensive trial coined Freedom showed the use of Denosumab successfully increased bone mineral density (BMD) at cortical bone sites, particularly the 1/3 radius skeletal site which does not typically respond to osteoporosis treatments. The Freedom trial was documented during 3 years of placebo/Denosumab administration and another 6 years of treatment for patients with Denosumab only. The incidence of wrist fracture and 1/3 radius BMD were examined in 2,207 women. The extended 6 years of data gleaned was deemed the Freedom Extension trial. Of the 2,207 women, all with varying degrees of wrist fracture, not one woman withdrew from the trial due to adverse effects. The female participants also received daily doses of both vitamin D and calcium in addition to either the placebo or Denosumab doses. The participants in the Freedom Extension trial experienced bone loss reversal, which resulted in bone mineral density gains at the 1/3 radius of 1.5 percent. An overwhelmingly positive conclusion was drawn by study investigators that treatment with Denosumab for at least 3 years was able to not only stop, but also reverse bone loss. Additionally, greater than 3 years of Denosumab therapy translated into both gains in BMD as well as lower wrist fracture rates in the future overall. Reversing the cortical bone loss in patients suffering from osteoporosis is key in the prevention of fractures and injuries for this susceptible patient population.

Age and bone massDenosumab, also known as the brand name Prolia, which is marketed by Amgen, is prescribed for women and men at risk for osteoporosis, although the majority of patients using Denosumab therapy are females who are postmenopausal. This drug is in the classification of monoclonal antibodies and there are few adverse effects associated with Denosumab. Commonly reported side effects include constipation, muscle pain and muscle weakness. The typical dosage of Denosumab is 60 milligrams, administered via one subcutaneous injection approximately every 6 months. Patients who are undergoing therapy with Denosumab are usually advised to take 1000 milligrams of calcium daily, as well as 400 IU of vitamin D daily. In addition to women who are at risk of osteoporosis due to menopause Denosumab is also prescribed for the following:

  • Postmenopausal women who are at high risk for fractures, specifically in need of a reduction in risk for vertebral and hip fractures.
  • Women who are at menopause or are postmenopausal and cannot tolerate other forms of treatment for the prevention of osteoporosis.
  • Therapy for women who are at risk of bone loss due to breast cancer therapy with aromatase inhibitors.
  • As a treatment for men who are at risk for osteoporotic bone fractures due to a current diagnosis of osteoporosis or who are at a very high risk of getting osteoporosis.
  • Treating men who have bone loss due to androgen deprivation therapy, as a result of nonmetastatic prostate cancer treatments.

LGM Pharma can assist clients as a supplier/distributor of the API Denosumab, CAS # 615258-40-7 for research and development purposes. Clients can be assured of quality API products and continuous support throughout the R&D process.

Products currently covered by valid US Patents are offered for R&D use in accordance with 35 USC 271(e) +A13(1). Any patent infringement and resulting liability is solely at buyer risk.

 

FDA Approves Bazedoxifene and Conjugated Estrogens to Treat Hot Flashes and Prevent Osteoporosis

Bazedoxifene 198481-32-2 FDA ApprovalOn October 3, 2013 the FDA approved the new medication Duavee, comprised of Bazedoxifene and conjugated estrogens (Premarin) to treat hot flashes in postmenopausal women. The unique ability of this novel treatment to curtail hot flashes and help prevent osteoporosis is encouraging for gynecologists and their female patients who are experiencing post-menopause. The combination of conjugated estrogens and the estrogen agonist Bazedoxifene is considered to be a safe alternative to debilitating hot flashes, which is a result of increased vasomotor activity.  This treatment is intended for women who are post-menopausal and still have a uterus, and should be used for a short period of time only. The dynamic combination of conjugated estrogens and Bazedoxifene is not intended as a first line treatment for osteoporosis, but it is an effectual and tolerable option for women who need both the hormonal assistance, and who are at a significant risk for this bone destroying disease. Studies have offered reassurance for women who may have concerns regarding risks of endometrial hyperplasia or uterine cancer after using this drug combination. The addition of Bazedoxifene to the conjugated estrogens curtails excessive growth of the uterine lining, making risks low for women concerned with their uterine cancer risk. Studies of Duavee have not revealed severe adverse events, and most women experience minimal side effects, which have included mild nausea, dizziness and stomach upset.

Approved as an easy to remember once daily pill, this combination treatment of Bazedoxifene and conjugated estrogens is available as a 20 mg/0.45 mg tablet. Patients who have had certain female cancers, blood clots or a history of stroke and heart attack are not candidates for this post-menopausal treatment.  Positive data emerged from Phase III clinical trials, which were coined SMART, or the Selective Estrogens, Menopause, And Response to Therapy program.  The FDA based their timely approval of this formidable combination treatment based on the excellent results from the Phase III SMART trial.

Of the women who participated in the SMART trial a significant 74 percent experienced a sizable reduction in their hot flashes after 12 weeks of treatment, as compared to 47 percent of women who received a placebo. Other trials of Duavee have revealed encouraging data regarding the bone density of women who were dosed with this post-menopausal treatment. Female participants in these aforementioned trials demonstrated greatly increased bone mineral density scores after between one and two years treatment with this conjugated estrogens and Bazedoxifene drug.  Patients can expect to see this novel treatment in pharmacies in the early half of 2014.

The FDA approval of conjugated estrogens and Bazedoxifene CAS# 198481-32-2,  is an exciting opportunity for research and development. LGM Pharma provides the Bazedoxifene API for research and development purposes. Clients can be assured of continuous support throughout the R&D process, as well as quality API products.

 

Products currently covered by valid US Patents are offered for R&D use in accordance with 35 USC 271(e)+A13(1). Any patent infringement and resulting liability is solely at buyer risk.

Vitamin D Analogues Clinically Useful for Several Conditions

Calcium Regulation
Calcium regulation in the human body. The role of vitamin D is shown in orange.

There are several active pharmaceutical ingredient products known as vitamin D analogues, which are derivatives of this powerful vitamin, designed to aid patients’ health and well being. Vitamin D is known by many people as the vitamin that helps to create strong bones, but this is just one of the benefits of vitamin D. As a key regulator of serum calcium levels, vitamin D is detected by bone and intestinal cell receptors, thus regulating the level of calcium in the blood stream while determining how much should be stored in the skeleton. This regulation is crucial, as calcium is responsible for a variety of physiological processes, not just building bone. A lack of vitamin D can be devastating, and promote the breakdown of bones in conditions such as rickets in children, and osteomalacia, a softening of bones leading to an increased risk of fracture, in adults. Vitamin D affects the immune system by interacting with some types of cells to dampen the immune response. This can be beneficial in cases where the immune system is over-reactive, as in autoimmune diseases including type 1 diabetes, multiple sclerosis and rheumatoid arthritis. Some studies have found that people living in regions with more sunlight have lower rates of these diseases, but it is not clear whether higher vitamin D levels are responsible.

The following vitamin D analogues are all calcium regulators, designed to increase blood calcium levels in patients:


Calcitriol, CAS number 32222-06-3
calcitriolCalcitriol, CAS number 32222-06-3 is a calcium regulator, which increases blood calcium levels by promoting the absorption of dietary calcium from the gastrointestinal tract. Calcitriol additionally aids the body in increasing the reabsorption of calcium, therefore reducing the loss of calcium in the urine. Bone cells referred to as osteoclasts are stimulated via this release of calcium from the bone when patients take calcitriol, and intestinal absorption of both calcium and phosphorus is increased as well. Known as the injectable drug Calcijex, marketed by Abbott Laboratories, calcitriol is earmarked for use in the management of hypocalcemia in patients undergoing chronic renal dialysis.

Alfacalcidol CAS number 41294-56-8
AlfacalcidolAlfacalcidol CAS number 41294-56-8 (or 1-hydroxycholecalciferol) has less of an effect on calcium metabolism than calcitriol, while having more potent effects on parathyroid hormone levels and immune system, including regulatory T cells. Alfacalcidol, an analogue of vitamin D, is used to heal bone fractures and to treat metabolic bone diseases by inhibiting bone resorption and/or favor bone mineralization and bone regeneration. It is available in capsules, oral drops and injection form.

Calcifediol, CAS number 19356-17-3
Calcifediol, 19356-17-3, LGM PharmaCalcifediol, CAS number 19356-17-3 is essentially a man-made form of vitamin D. Calcifediol is crucial in helping patients to attain and maintain proper levels of calcium and phosphorus. Those patients with kidney disease may find the use of calcifediol advantageous, as it helps to keep calcium levels stable and allow normal bone growth. Marketed by Organon as Calderol, calcifediol is available in capsules to be taken orally, as either a 0.02 or a 0.05 milligram dose.

For patients with Psoriasis and Vitiligo, vitamin D analogues can be extremely efficacious:


Maxacalcitol, CAS number 103909-75-7
Maxacalcitol, 103909-75-7, LGM PharmaMaxacalcitol, CAS number 103909-75-7 is an anti-psoriatic vitamin D analogue, as well as a vitamin D3 analogue. In studies comparing maxacalcitol with either Calcipotriol or Tacalcitol, maxacalcitol proved to be a stronger opponent, offering a ten times greater efficacy at suppressing keratinocyte proliferation. One particular double-blind, randomized study involved a once-daily topical dose of maxacalcitol in patients with mild to moderate chronic plaque psoriasis. The concentrations of maxacalcitol ointment included 6, 12.5, 25 and 50 micrograms, with greatest effect noted for the 25 microgram dose. The 50 microgram once daily dose of calcipotriol ointment offered a comparative effect when compared to the 25 microgram dose of maxacalcitol, of which 55 percent of patients reported remarkable improvement in their psoriasis.

Calcipotriol CAS number 112965-21-6
Calcipotriol, 112965-21-6, LGM PharmaCalcipotriol CAS number 112965-21-6 continues to be a viable contender for skin conditions like vitiligo. Known as the brand name Dovonex, marketed by LEO Laboratories, Ltd., for Warner Chilcott, calcipotriol remains a respected topical dermatologic product. In The British Journal of Dermatology study results were published documenting the conclusions from a clinical trial, which determined the effectiveness and tolerability of calcipotriol cream, used as a monotherapy in conjunction with psoralen plus ultraviolet A (PUVA), in the treatment of vitiligo patients. Patients were treated with 50 micrograms twice-daily of topical calcipotriol monotherapy or twice-daily topical calcipotriol, 50 micrograms, along with topical or oral 8-methoxypsoralen PUVA three times weekly. Results were positive, with 77 percent of patients experiencing between a 30-100 percent marked improvement in their condition, with no recorded adverse effects. Those patients treated with the combination therapy also demonstrated improvement and indicated a positive response.

Tacalcitol CAS number 57333-96-7
Tacalcitol 57333-96-7Tacalcitol CAS number 57333-96-7 is another anti-psoriatic, synthetic vitamin D3 analogue. Marketed outside the U.S. under several names, including Curatoderm and Bonalfa, tacalcitol is a capable product. As plaque psoriasis is a skin disorder, caused by cells in the outer layer of the skin multiplying too quickly, tacalcitol is efficient and helps control the production of new skin cells when old cells die, thus controlling the effects of this condition.

With infrequent unfavorable effects, maxacalcitol, calcipotriol and tacalcitol are all prosperous products with great promise for the treatment of psoriasis and vitiligo.

Patients suffering from secondary hyperparathyroidism will find these antineoplastic API’s helpful:


Doxercalciferol, CAS number 54573-75-0
Doxercalciferol 54573-75-0Doxercalciferol, CAS number 54573-75-0, another synthetic analogue of vitamin D, offers potential antineoplastic activity for treatment of secondary hyperparathyroidism. Patients with low calcium concentrations find that their parathyroid gland secretes the parathyroid hormone, or PTH, which activates vitamin D in the body. By targeting osteoblasts to stimulate skeletal growth, doxercalciferol also acts on parathyroid glands to suppress PTH synthesis and secretion.

Paricalcitol, CAS number 131918-61-1
Paricalcitol 131918-61-1Paricalcitol, CAS number 131918-61-1 is also a noteworthy anti-hyperparathyroidism product. As an analog of calcitriol, the active form of vitamin D, it acts as an agonist for the calcitriol receptor and thus lowers the blood parathormone level. Also known as Zemplar, and marketed by Abbott laboratories, paricalcitol is utilized for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure.

Both Paricalcitol and Doxercalciferol increase calcium absorption in the small intestine, and prove their efficacy not only by promoting the release of calcium from bones, but also reducing calcium excretion in the kidneys.

With the biology, as well as the gene regulatory properties of vitamin D more fully understood by researchers, the use and experimentation with vitamin D analogues are in the forefront of medical technology. The potential unique and designer formulations of the vitamin D analogues offer personalized therapeutic potential for patients suffering from secondary hyperparathyroidism, plaque psoriasis, vitiligo, calcium deficiences, as well as other autoimmune conditions related to a lack of vitamin D. The aforementioned patient populations stand to benefit greatly from these conceivable salubrious discoveries.

Products currently covered by valid US Patents are offered for R&D use in accordance with 35 USC 271(e)+A13(1). Any patent infringement and resulting liability is solely at buyer risk.

Denosumab is Poised to be a Boon to Bone Health

Denosumab, CAS number 615258-40-7, offers divergent options for researchers working with this monoclonal antibody. The scope of efficacy for denosumab is wide, with one of it’s uses being an approved treatment of osteoporosis in women, particularly those women who are post menopausal. Known as the brand Prolia®, which is marketed by Amgen, denosumab is effectively geared for women who are at high risk for fractures or who cannot tolerate other osteoporosis medications. Denosumab is also known as the brand Xgeva®, which is marketed by Amgen as well, and is used to prevent bone fractures in patients with tumors that have spread to the bone. The capabilities of denosumab are varied, showing virtue in the prevention of skeletal-related events in patients with bone metastases from solid tumors, and the ability to slow down the bone-breakdown process in women with osteoporosis.

Studies of denosumab, known as Prolia, indicate that post menopausal women who received the twice a year injections showed marked improvement in both bone density and less fracture incidence. This three year study gleaned information as to how denosumab is thought to work, and it is believed to target a chemical signal called RANK ligand, which is an integral part of the body’s natural process for breaking down bone. Reported side effects from clinical trial participants using Prolia were back pain, high cholesterol levels, urinary bladder infections, rashes, and a higher risk of serious infections.

Denosumab, when taken as the brand Xgeva, is efficacious treatment for patients with cancerous or solid tumors who are at risk for skeletal fractures. It is clearly defined as not being indicated for the prevention of skeletal-related events in patients with multiple myeloma. Administered as a subcutaneous injection of 120 milligrams every four weeks, denosumab is generally well tolerated. Potential adverse effects include hypocalcemia, dyspnea, fatigue and nausea. In May 2011 Amgen revealed great success with Phase 3 trials of Xgeva, and announced a documented rate of bone metastasis-free survival in men with prostate cancer, by administering Xgeva. Xgeva, or denosumab, demonstrated the ability to prevent bone metastases in the men studied, with back pain being the most commonly reported adverse effect.

The FDA has approved denosumab for use in the management of osteoporosis, as well as the prevention of skeletal related events in patients with breast and prostate cancers that have metastasized to the bones. These approvals for both Prolia and Xgeva are only the beginning of exciting research and development underway for denosumab. LGM Pharma works in close collaboration with manufacturers worldwide, and is a preferred supplier of the API denosumab for research and development programs.

Products currently covered by valid US Patents are offered for R&D use in accordance with 35 USC 271(e)+A13(1). Any patent infringement and resulting liability is solely at buyer risk.