Category Archives: Drugs

Bisphosphonates Reduce Mortality in Women


Osteoporosis medication and reduced mortality risk in elderly women and men.

Osteoporotic fractures are associated with premature mortality. Antiresorptive treatment reduces refracture but mortality reduction is unclear.
The objective of the study was to examine the effect of osteoporosis treatment [bisphosphonates (BP), hormone therapy (HT), and calcium ± vitamin D only (CaD)] on mortality risk.
This was a prospective cohort study (April 1989 to May 2007).
The study was conducted with community-dwelling elderly (aged 60+ yr) subjects in Dubbo, a semiurban city, Australia.
Subjects included 1223 and 819 women and men in the Dubbo Osteoporosis Epidemiology Study.
Mortality according to treatment group was recorded.
There were 325 (BP, n = 106; HT, n = 77; CaD, n = 142) women and 37 men (BP, n = 15; CaD, n = 22) on treatment. In women, mortality rates were lower with BP 0.8/100 person-years (0.4, 1.4) and HT 1.2/100 person-years (0.7, 2.1) but not CaD 3.2/100 person-years (2.5, 4.1) vs. no treatment 3.5/100 person-years (3.1, 3.8). Accounting for age, fracture occurrence, comorbidities, quadriceps strength, and bone mineral density, mortality risk remained lower for women on BP [hazard ratio (HR) 0.3 (0.2, 0.6)] but not HT [HR 0.8 (0.4, 1.8)]. For 429 women with fractures, mortality risk was still reduced in the BP group [adjusted HR 0.3 (0.2, 0.7)], not accounted for by a reduction in subsequent fractures. In men, lower mortality rates were observed with BP but not CaD [BP 1.0/100 person-years (0.3, 3.9) and CaD 3.1/100 person-years (1.5, 6.6) vs. no treatment 4.3/100 person-years (3.9, 4.8)]. After adjustment, mortality was similar, although not significant [HR 0.5 (0.1, 2.0)].
Osteoporosis therapy appears to reduce mortality risk in women and possibly men.

Center JR, Bliuc D, Nguyen ND, Nguyen TV…
J. Clin. Endocrinol. Metab. Apr 2011
PMID: 21289270

Low-Dose Alendronate Effect is Similar to Standard-Dose in Chinese Women with Bone Loss


Effect of low-dose alendronate treatment on bone mineral density and bone turnover markers in Chinese postmenopausal women with osteopenia and osteoporosis.

The aim of this study was to evaluate the effect of low-dose alendronate (ALN) treatment on bone mineral density (BMD) and bone turnover markers in Chinese postmenopausal women with osteopenia and osteoporosis.
This study was a large-sample, randomized, open-label, prospective, multicenter, clinical trial with a 12-month follow-up. A total of 639 postmenopausal women (aged 62.2 ± 7.0 y) with osteopenia or osteoporosis were randomized into two groups: low-dose ALN (70 mg every two weeks) and standard-dose ALN (70 mg weekly). All patients were also supplemented with calcium (600 mg) and vitamin D3 (125 IU) daily. BMD (measured by dual-energy x-ray absorptiometry; Hologic and Lunar) and levels of serum bone turnover markers (bone resorption marker, carboxy-telopeptide of type I collagen; bone formation marker, alkaline phosphatase) were assessed at baseline and at 3, 6, and 12 months of treatment. BMD and bone turnover markers were compared between the baseline and the end of treatment, and the changes in BMD and bone turnover markers were also compared between the low-dose ALN group and the standard-dose ALN group.
No significant differences in age, years since menopause, body mass index, BMD, 25-hydroxy vitamin D level, and serum biochemical markers were found at baseline between the two dose groups. A total of 558 (87.3%) and 540 (84.5%) women completed the treatment at the 6th and 12th months, respectively. After the 12-month treatment, lumbar spine and hip BMD increased and serum bone turnover markers decreased significantly in both of the treatment groups (P < 0.01), and no differences in percentage changes in BMD at the lumbar spine, femoral neck, and hip were found between the low-dose group (5.60%, 3.87%, and 3.28%, respectively) and the standard-dose group (5.07%, 2.93%, and 3.80%, respectively; P > 0.05). However, levels of serum alkaline phosphatase and carboxy-telopeptide of type I collagen in the standard-dose group decreased moderately compared with those in the low-dose group (P < 0.05 and P < 0.01). The women tolerated the two doses of ALN quite well. Adverse effects were similar in the two groups.
Treatment with low-dose ALN (70 mg every two weeks) in women with postmenopausal osteopenia or osteoporosis effectively increases lumbar spine and hip BMD, similar to treatment with standard-dose ALN. Low-dose ALN may be a cost-effective and safe protocol for treating osteopenia or osteoporosis in Chinese women.

Li M, Zhang ZL, Liao EY, Chen DC…
Menopause Jan 2013
PMID: 22968256

Review: New Treatments


New developments in the treatment of osteoporosis.

The last 25 years have seen the development of a plethora of new, effective agents for the treatment of osteoporosis. These agents reduce the risk of spine fractures by up to 70%, hip fractures by 40-50% and non-vertebral fractures by up to 50-80%. Amino-bisphosphonates, taken orally or intravenously, remain the dominant treatment modalities for osteoporosis. These so-called anti-resorptive or anti-catabolic agents stabilize the skeleton and reduce fracture risk in osteoporotic as well as osteopenic individuals. A monoclonal antibody against receptor activator of nuclear factor κB ligand, Denosumab, constitutes a new anti-resorptive agent recently approved worldwide. In younger postmenopausal women, low-dose estrogen or estrogen/progestin still has a place for short-term (up to 5 years) preservation of bone mass, especially in women with menopausal symptoms. Likewise, selective estrogen receptor modulators should be considered in younger postmenopausal women, especially those at increased risk of breast cancer. Anabolic (bone forming) regimens, of which parathyroid hormone is the only agent currently available, aid in the build up of new bone, increase bone mass and improve bone architecture. In cancellous bone, 30-60% increases of bone mass have been documented, but cortical bone thickness also increases. These improvements lead to profound reduction in fracture rates in both the axial and appendicular skeleton. Owing to cost and the need for parenteral administration, in most countries these agents are reserved for severe osteoporosis with multiple fractures.

Eriksen EF, Halse J, Moen MH
Acta Obstet Gynecol Scand Jun 2013
PMID: 22646526

Bisphosphonates Showed the Smallest Increase In Fracture Rate Over 10 Years


Ten-year fracture risk in the assessment of osteoporosis management efficacy in postmenopausal women: a pilot study.

The aim of the reported longitudinal, retrospective pilot study was to establish changes in 10-year fracture risk in postmenopausal women with respect to applied fracture management.
A group of 191 postmenopausal women with a mean age of 68.76± 6.72 years was divided into subgroups. The subgroups were made up of untreated patients (n = 41), patients treated with vitamin D plus calcium (n = 46), and patients treated with bisphosphonates, vitamin D and calcium (n = 104). Repeated densitometric measurements and clinical data were taken into consideration (both baseline and follow-up). Ten-year fracture risk was established, using FRAX(TM) and Garvan nomograms. The mean follow-up period was 2.01±1.87 years.
Generally, the mean fracture probability increased in the studied women over the observation period. Patients on bisphosphonate therapy demonstrated the smallest increase in fracture probability. The probability rate for either any fractures or hip fractures decreased when the T-score increased. A diminished number of falls non-significantly decreased the probability for hip fractures and any fractures.
Ten-year fracture risk increased irrespective of applied management, while a decreased risk was observed only in women with improved bone status.

Pluskiewicz W, Drozdzowska B, Adamczyk P
Climacteric Feb 2013
PMID: 22335356

Glakay Vitamin K2 (MK-4) Capsules 15mg

Glakay is the trade name for the prescription Vitamin K2 (MK-4) treatment for osteoporosis in Japan. It is manufactured by Eisai Co. It was approved in 2005 by the Japanese Ministry of Health & Welfare which is the equivalent of the FDA in Japan.

Glakay is 15mg MK-4 taken 3 times per day. The total dose is 45mg per day.

2005 Glakay Press Release
Glakay Package Insert

Vitamin K2 (MK-4) Suppresses RANKL Alone or With Bisphosphonates


Osteoclast inhibitory effects of vitamin K2 alone or in combination with etidronate or risedronate in patients with rheumatoid arthritis: 2-year results.

To investigate the effects of vitamin K2 (Vit K2) alone or in combination with etidronate and risedronate on bone loss, osteoclast induction, and inflammation in patients with rheumatoid arthritis (RA).
Subjects comprised 79 patients with RA who were receiving prednisolone, divided into 3 groups: Group K, Vit K2 alone; Group KE, Vit K2 plus etidronate; and Group KR, Vit K2 plus risedronate. During a 24-month treatment and followup period, levels of N-terminal telopeptide of type I collagen (NTx) and bone alkaline phosphatase were measured. Bone mineral density (BMD) of the 3 groups was measured using dual-energy x-ray absorptiometry. Damage score to fingers on radiographic findings were measured according to the Larsen method. Serum levels of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) were measured.
Falls in rate of change of BMD decreased after 18 months in groups KR and KE. Larsen damage scores indicated a significant difference between Group KE and other groups. Significant decreases in serum NTx were observed in groups KE and KR at all timepoints, but not in Group K. Levels of RANKL decreased significantly in all 3 groups.
Vit K2 alone or in combination with bisphosphonates for treatment of osteoporosis in patients with RA may inhibit osteoclast induction via decreases in levels of RANKL.

Morishita M, Nagashima M, Wauke K, Takahashi H…
J. Rheumatol. Mar 2008
PMID: 18260178

Diosgenin and Lovastatin Prevent Bone Loss in Ovariectomized Rat


Osteoprotective effect of Monascus-fermented dioscorea in ovariectomized rat model of postmenopausal osteoporosis.

This experiment established the ovariectomized (OVX) rat model of postmenopausal osteoporosis and examined the effect of the oral administration of different dosages of dioscorea, red mold dioscorea (RMD), and soy isoflavones on bone mineral density (BMD). Three months after osteoporosis had been induced and 4 weeks after feeding had begun, the tibia and femur BMD of OVX rats administered RMD showed significant increases compared with that of all other groups of OVX rats. Closer examination using microcomputed tomography also revealed that the RMD-administered rats had denser trabecular bone volume and a higher trabecular number compared to all other rat groups. Reconstructed 3D imaging indicated increases in cancellous bone mineral content, cancellous bone mineral density, and cortical bone mineral content of the proximal tibia in OVX rats. These findings indicate that administration of monacolin K and phytoestrogen diosgenin could prevent bone loss induced by estrogen deficiency.

Chiang SS, Chang SP, Pan TM
J. Agric. Food Chem. Sep 2011
PMID: 21800902

Phenytoin Lowers Vitamin D and Increases Fractures


Bone mineral density and serum levels of 25 OH vitamin D in chronic users of antiepileptic drugs.

The aim of this cross sectional study was to evaluate bone mineral density (BMD) and serum levels of 25-hydroxy vitamin D (25OHD) in a group of patients taking antiepileptic drugs (AED) for a seizure disorder. Between May-2001 and January-2003, we evaluated 58 patients (40 women/18 men), 34.4+/-6 years old living in Curitiba or in its metropolitan area, on antiepileptic therapy for 2 to 38 years (10 on monotherapy /48 on multiple drugs regime). The group was matched by age, gender, and bone mass index to 29 healthy subjects (20 women/ 9 men); 34.2+/-5.9 years old. Medical history and physical exam were performed on all subjects with particular information sought about fractures and risks factors for osteoporosis. Blood samples were collected for total serum calcium, albumin, phosphorus, creatinine, total alkaline phosphatase, and liver function tests. BMD of the lumbar spine, femur and forearm was determined by dual energy X-ray absorptiometry (DXA, Hologic QDR 1000). Between February and April-2003, other blood samples were collected to measure 25OHD, intact paratohormone (PTH) and calcium. Unemployment and smoking history were more frequent among patients than among controls (p<0.05). Fifteen patients had a fracture history, all of which occurred during a seizure. The BMD of the lumbar spine (0.975+/-0. 13 g/cm2 vs. 1.058+/-0.1 g/cm2; p<0.03) and of the total femur (0.930+/-0.1 g/cm2 vs. 0.988+/-0.12 g/cm2; p<0.02) was lower in patients than in controls. In 63.5% of patients and in 24.1 % of controls a T-score < -1.0 in at least one site was seen. The AED users had higher total alkaline phosphatase and lower 25OHD (p<0.02). No correlations between BMD and 25OHD were found. The use of phenytoin was correlated with a greater incidence of fractures (RR: 2.38). We conclude that patients on chronic use of AED have alterations in bone metabolism characterized in this study by lower BMD of the lumbar spine and total femur and lower serum concentrations of 25OHD.

Kulak CA, Borba VZ, Bilezikian JP, Silvado CE…
Arq Neuropsiquiatr Dec 2004
PMID: 15608949 | Free Full Text

Phenytoin Lowers Vitamin D


Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy.

Antiepileptic drugs (AEDs) may have adverse effects on bone mineral density (BMD) and metabolism. We previously reported biochemical evidence of increased bone turnover in premenopausal women with epilepsy on phenytoin monotherapy compared with those on carbamazepine, lamotrigine, and valproate. We therefore hypothesized that rates of bone loss would be higher in young women treated with phenytoin.
Ninety-three premenopausal women with epilepsy receiving a single AED (carbamazepine, lamotrigine, phenytoin, or valproate) participated. Subjects completed nutritional and physical activity questionnaires. Biochemical indices of bone and mineral metabolism and BMD of the proximal femur and lumbar spine were measured at baseline and 1 year.
Participants reported high calcium intake (>1,000 mg/day) and were physically active. Significant loss (2.6%) was seen at the femoral neck in the phenytoin group. BMD remained stable in the other AED groups. Bone turnover markers and calciotropic hormones were unchanged after 1 year in all groups except for a significant decline in urine N-telopeptide in the phenytoin group. In women receiving phenytoin, lower serum 25-hydroxyvitamin D concentrations were associated with higher parathyroid hormone, bone alkaline phosphatase, and urine N-telopeptide levels, a biochemical pattern consistent with secondary hyperparathyroidism and increased remodeling.
In this study, young women treated with phenytoin had significant femoral neck bone loss over 1 year. In contrast, those treated with carbamazepine, lamotrigine, and valproate did not have detectable adverse effects on bone turnover or bone mineral density. These results raise concerns about the long-term effects of phenytoin monotherapy on bone in young women with epilepsy.

Pack AM, Morrell MJ, Randall A, McMahon DJ…
Neurology Apr 2008
PMID: 18443309

Phenytoin Associated with Increased Rate of Loss of Calcaneus Bone


Antiepileptic drug use increases rates of bone loss in older women: a prospective study.

To test the hypothesis that older women with antiepileptic drug (AED) use have increased rates of bone loss. AED use was ascertained and calcaneal and hip bone mineral density (BMD) measured in a cohort of 9,704 elderly community-dwelling women enrolled in the Study of Osteoporotic Fractures, and they were followed prospectively for changes in BMD.
Current use of AED was assessed by interview, with verification of use from medication containers at baseline and follow-up examinations. Women were classified as continuous users, partial (intermittent) users, or nonusers. Rates of change in BMD were measured at the total hip and two subregions (average 4.4 years between examinations) and at the calcaneus (average 5.7 years between examinations).
After adjustment for confounders, the average rate of decline in total hip BMD steadily increased from -0.70%/year in nonusers to -0.87%/year in partial AED users to -1.16%/year in continuous AED users (p value for trend = 0.015). Higher rates of bone loss were also observed among continuous AED users at subregions of the hip and at the calcaneus. In particular, continuous phenytoin users had an adjusted 1.8-fold greater mean rate of loss at the calcaneus compared with nonusers of AED (-2.68 vs -1.46%/year; p < 0.001) and an adjusted 1.7-fold greater mean rate of loss at the total hip compared with nonusers of AED (-1.16 vs -0.70%/year; p = 0.069).
Continuous AED use in elderly women is associated with increased rates of bone loss at the calcaneus and hip. If unabated, the rate of hip bone loss among continuous AED users is sufficient to increase the risk of hip fracture by 29% over 5 years among women age 65 years and older.

Ensrud KE, Walczak TS, Blackwell T, Ensrud ER…
Neurology Jun 2004
PMID: 15184613