NEW DEVELOPMENTS IN PARATHYROID AND BONE DISEASE        HOME
by  Dr Pamela Taxel, Div of Endocrinology and Metabolism, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030

Holick MF, Vitamin D deficiency. N Engl J Med. 2007 Jul 19;357(3):266-81.
This article is a complete overview of the role of vitamin D in skeletal health as well as the more recent understanding of its important non-endocrine effects. As many body tissues possess the vitamin D receptor and the ability to convert 25-OH vitamin D (the body’s storage form) to the active form, 1,25 dihydroxy-vitamin D3, a number of crucial roles in infectious, autoimmune, cancer and cardiovascular disorders has recently been elucidated.
Vitamin D and bone health: Vitamin D deficiency is still a major issue regarding skeletal health despite current fortification of food sources and the advances in recognizing and treating rickets and osteomalacia. The optimal serum vitamin D level is not agreed upon by experts; however, serum levels of less than 20 ng/ml are considered deficient. Studies of the efficacy of vitamin D on fracture prevention are mixed. In studies where supplementation with 7-800 IU per day were included, risk of hip fractures was reduced by 26% and non-vertebral fractures by 23%. Thus, optimal prevention of both non-vertebral and hip fractures occurred in trials providing 7-800 IU vitamin D per day and in women who had baseline levels less than 17 ng/ml and rose above 40 ng/ml.
Muscle weakness is also known to be an effect of vitamin D deficiency. Trials have shown improved performance speed and muscle strength when levels rose from insufficient to sufficient levels of 40 ng/ml or more. Fall frequency has also been significantly reduced in trials where subjects have received 800 IU /day of vitamin D with their calcium.
Non-Skeletal Actions of Vitamin D: Immune cells and many tissues possess the machinery to convert 25 to 1,25 OH2D3. 1,25 is a potent immune modulator and plays an important role in response to certain infectious agents such as M Tuberculosis. It also influences over 200 genes responsible for cellular proliferation, apoptosis, differentiation and angiogenesis. Prospective and retrospective data indicate that 25 OH vitamin D levels below 20 ng/ml are associated with increased risk of colon, prostate and breast cancer. In the Nurses Health Study the odds for colorectal cancer were inversely associated with levels of 25-OH vitamin D (the odds ratio at 40 ng/ml was 0.53). Levels of 25-OH vitamin D have also been associated with a reduced risk of multiple sclerosis, rheumatoid and osteoarthritis. Studies have also suggested that vitamin D supplements in children can reduce the risk of type 1 diabetes mellitus. Furthermore, the author also points out that chronic kidney disease patients should have 25-OH vitamin D serum levels of 30 ng/ml, as the parathyroid glands will convert 25-OH to 1,25 OH2D3 inhibiting expression of PTH and secondary hyperparathyroidism. 
Recommendations for vitamin D intake: Most experts agree that approximately 800-1000 IU per day are required for children and adults without sun exposure. Supplementation with Vitamin D3 is more effective than D2 in maintaining normal 25-OH vitamin D serum levels. The use of high dose D2 in the form of 50,000 units weekly for repletion and then monthly for maintenance is suggested. Another effective and safe regimen is the use of 1000 to 3000 IU of vitamin D3 daily. Lactating women require 4000 IU D3 per day to maintain 25-OH vitamin D levels above 30 ng/ml and to transfer sufficient amounts of vitamin D to their breast fed babies.  Sun exposure, if not excessive can provide adequate amounts of vitamin D3 for as short as 5-30 minutes twice per week.
Vitamin D toxicity is very rare but can occur if inadvertent or purposeful ingestion occurs. Doses of up to 10,000 units per day of D3 up to 5 months have not been associated with toxicity. Thus, the margin of safety seems to be wide.
In conclusion, recommendations for adequate vitamin D ingestion are currently inadequate and should be increased to at least 800 IU/day of vitamin D per day.  This will insure most people with sufficient levels and the important endocrine and non-endocrine benefits of this vitamin.

 Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S; the HORIZON Recurrent Fracture Trial. Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture. N Engl J Med. 2007 Sep 26.
Mortality after hip fractures is as high as 15-25% within the first year after hip fracture.  One major source of significant morbidity after hip fractures is subsequent fractures. Studies show that a low percent of patients receive pharmacologic treatment after fracture, and many are non-compliant with oral anti-resorptives. The current study sought to evaluate new clinical fractures and mortality in subjects with recent hip fractures who were randomly assigned to receive either 5 mg/year of intravenous zoledronic acid (ZA, N=1065) or placebo (PL, N=1062). All patients received supplemental calcium and vitamin D.
At baseline, the mean age of the study population was 74.5 years: 90% of each group was White; 6.6% Hispanic and 1% Black; seventy-five percent were women. Femoral neck bone mineral density was osteoporotic in 41 and 42%, and osteopenic in 35 and 34%, respectively (PL vs ZA groups, respectively). The median follow-up was 1.9 years.
Four hundred and twenty-four new fractures occurred during the follow-up period. There were 8.6% new clinical fractures in the ZA and 13.9% in the PL groups. This represents an absolute fracture reduction of 5.3% and a relative reduction of 35%. Rates of new clinical vertebral fracture were 1.7 and 3.8%; new non-vertebral fractures 7.6% and10.7% in the ZA and PL groups, respectively. Two percent and 3.5% of those in the ZA and PL groups experienced new hip fractures with a relative risk reduction of 30%, although non-significant. 9.6% and 13.3% of the ZA and PL groups died, a significant decrease of 28% from all cause mortality. 
Both groups experienced similar frequency of adverse events (38-42%).  ZA group patients experienced more pyrexia, myalgia and bone or musculoskeletal pain than those receiving PL. There was no difference in incidence of atrial fibrillation, stroke or myocardial infarction between the groups; osteonecrosis of the jaw was not reported in any subjects. There were few reports of hypocalcemia, because the protocol included a loading dose of vitamin D and 800-1200 IU was given daily.
The authors point out that the studied group is younger than the usual population with hip fractures, as overall one-year mortality was less than expected. In addition, the very important caution that patients receiving zoledronic acid must be vitamin D sufficient in order to avoid potential hypocalcemia was also emphasized.  In conclusion, treatment with annual zoledronic acid reduced the risk of subsequent clinical fractures including non-vertebral and vertebral fractures. Although hip fracture reduction was not clinically significant, overall survival was increased. 



Glorieux FH. Experience with bisphosphonates in Osteogenesis Imperfecta. Pediatrics, 119: Supplement 2, March ‘07 
This article reviews the advances made in the last 14 years in the bone manifestations of Osteogenesis Imperfecta (OI) a genetic disorder of type 1 collagen that leads to decreased bone mass, fractures, pain and decreased mobility and function. OI can occur as a lethal or mild form, and mutations in the COL1A1 or COL1A2 gene have been described.  Search for other mutations has been actively pursued.
The use of bisphosphonates in children with OI, specifically with cyclic intravenous pamidronate q 2-4 months over the past decade has had significant impact on the bone manifestations of OI. Bone pain is often decreased and in many cases disappears within 1-2 weeks of the initial infusion. Bone density at the lumbar spine improves significantly, even when accounting for volumetric growth. Fracture incidence decreased from 2.3 to 0.6 events per year in the first report of this author. Significant fracture reduction has also been seen in children under 2 years of age.
One major concern regarding bisphosphonate therapy is that the decreased bone remodeling which occurs could lead to slowing of longitudinal height; however, this has not been the case. Furthermore, histomorphometric studies have shown gains in cortical thickness (88%) and trabecular volume(46%) after 2.4 years of treatment. The potential negative impact of reduced bone turnover caused by bisphosphonates has not been completely evaluated. This may include slower healing after osteotomies and delayed removal of damaged bone matrix. The author cautions that results of clinical trials may be influenced by a number of factors including severity of disease ambulation status and social environment; therefore, treatment success may mean higher fracture rates.
In conclusion, in up to 7 years of treatment, cyclic iv pamidronate has been determined to be safe (in regard to renal function), to improve bone pain and muscle force, increase bone density in both trabecular and cortical compartments and produce an overall gain in growth rate. These improvements have had a significant impact on moderate to severe OI.  However, concerns regarding length of time necessary to treat individual patients, decreased bone remodeling and potential delay of healing sites still exist.  In addition, long-term sequelae of bisphosphonates (eg. for pregnancy) which remain in bone for a long time also remain.

 

Cabral WA, Chang W, Barnes AM, et.al. Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet. 2007 Mar;39(3):359-65. 
Osteogenesis imperfecta (OI) is a skeletal disorder caused by mutations in the COL1A1 and COL1A2 genes through dominant inheritance. However, other candidate genes have been suspected in causing recessive forms of severe OI.  It is currently known that two other proteins, human cartilage-associated protein (CRTAP) and cyclophilin B are required for normal collagen structure. These proteins form a complex with prolyl 3-hydroxylase, P3H1, an enzyme with several known functions, one of which is the hydroxylation of a proline residue on type I collagen. CRTAP -/- mice develop severe bone dysplasia and abnormal type 1 collagen (Morello et al.). Additional evidence for this has come from a report of a recessive form of OI (severe or lethal) found in 3 of 10 children in which subjects were determined to have non-collagen primary defects.  They had CRTAP deficiency (null mutations), a gene that encodes for one type of post-translational modification of type 1 or 2 collagen, as shown by low CRTAP mRNA, lack of this protein and minimal P3H1 action(ref Barnes).
Thus, it was hypothesized that abnormal enzyme activity or defective P3H1would result in severe bone dysplasia. The current article reports the first 5 cases of one such mutation in the LEPRE1 gene which encodes P3H1. The mutation in this gene leads to a premature termination codon and minimal production off mRNA and protein.  The absence of P3H1 affects folding of type 1 collagen helix, leading to defective collagen structure. Affected probands demonstrated abnormal electrophoretic migration of collagen chains caused by an increased percent of hydroxylated lysine residues, or “overmodification.”
The phenotype of this bone disorder in the probands overlaps with lethal/severe OI but has several different features. These include white sclerae, long hands compared with forearms, round face and short barrel chest. Prenatal x-rays show undermineralized ribs and long bones. Thus, P3H1 is thus crucial for normal bone development and collagen helix formation, and the authors suggest that defects in LEPRE1 should be classified as Type VIII OI.
 Morello R, Bertin TK, Chen Y, et.al.CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell. 2006 Oct 20;127(2):291-304.
Barnes AM, Chang W, Morello R, et.al. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med. 2006 Dec 28;355(26):2757-64.

 

Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: the risedronate and alendronate (REAL) cohort study. Silverman SL, Watts NB, Delmas PD, Lange JL, Lindsay R. Osteoporos Int. 2007 Jan;18(1):25-34.  8 March 2007 

In this observational study, the investigators assessed the incidence of hip and nonvertebral fractures among women in the first year following treatment with once-a-week risedronate or alendronate. To ascertain fracture data in women ages 65 and older, commercially available datasets from multiple major U.S. health plans were analyzed. All subjects were enrolled in the plans between July 2002 and September 2004.  Adherence was determined by time between prescription refills (or gaps in prescription refills).  Women with evidence of Paget’s disease, malignant neoplasm or used bisphosphonates during the 6-month history period prior to enrollment were excluded from the study.
    For this analysis, baseline through one year data from 21,615 women treated with alendronate (ALN) and 12,215 treated with risedronate (RIS) were reviewed.  The incidence of fracture 12-months before initiation of bisphosphonates was similar with the exception that the RIS group had a statistically higher diagnosis of hip fracture than the ALN group.  In addition, at baseline, the RIS group was older, had a greater incidence of  rheumatoid arthritis and historically had a greater past use of glucocorticoids, all factors that could increase their risk of fracture. However, the RIS group had greater past use of calcitonin or and raloxifene which could potentially decrease fracture risk.  When the investigators evaluated fracture incidence 12-months before initiation of bisphosphonates, they noted that the cohorts were similar in fracture incidence with the exception that the RIS group had a statistically higher diagnosis of hip fracture than the ALN group. 
    The main outcome measures were 6 and 12-month incidence of hip and nonvertebral fractures.  After exclusion of traumatic fractures, there were a total of 109 hip and 507 nonvertebral fractures during the observation period. Nonvertebral fractures included wrist (30%), hip (21%), leg (17%), pelvis (15%) humerus (14%) and clavicle (3%).   At 3-months, both groups had overall similar fracture incidence.  At 6 and 12 months the RIS cohort had 19% (p=.05) and 18% (P= .03) lower incidence, respectively, of all nonvertebral fractures. After 3-months, both groups had an overall similar hip fracture incidence; at 6 and 12-months the RIS had 46% (p=.02) and 43% (p=.01) lower incidence, respectively, of hip fractures. Both groups had 41 % of the original cohort that was “censored” due to lack of adherence.
    The strength of this study is that it is a post-marketing survey with real world application and generalizability. The cohorts have similar fracture incidence in the first 3 months, as is seen in randomized controlled trials (RCTs), adding strength to the findings.  At the outset, the RIS group had greater percentage of risk factors for fracture, that may have biased this cohort toward more fractures; however, this was not observed. The RIS cohort also had higher prior use of medications known to reduce vertebral fractures that may have influenced these observations.  Since data were only available through medical claims, differences in fracture risk such as bone density, prior long term fracture history, smoking, family history, calcium and vitamin D intake or calcium metabolic status that may have influenced the outcomes were not known. Other characteristics usually controlled for in RCTs were also not available from the claims data, and may have produced inherent biases which influenced the results. In addition, the follow-up period of twelve months is of short duration. Most patients prescribed bisphosphonates remain on them for 5-10 years.  Thus, the current findings, while important, should be interpreted with some degree of caution.  A mechanism for these findings is not suggested by the investigators and would be intriguing. Further follow-up of these cohorts to confirm these findings would be optimal, although on a practical level, perhaps difficult. In conclusion, it appears that patients receiving RIS in the first year of treatment are better protected from hip and nonvertebral fractures.

28 Jan 07
Lewiecki EM, Laster AJ. Clinical review: Clinical applications of vertebral fracture assessment by dual-energy x-ray absorptiometry. J Clin Endocrinol Metab. 2006 Nov;91(11):4215-22. Epub 2006 Aug 29.
Vertebral Fracture Assessment (VFA) is a technology currently available for the diagnosis of vertebral fractures (VFs) that can be performed as part of a routine Dual-Energy X-ray Absorptiometry (DXA) measurement. The current review evaluates the utility of this technology compared to other techniques such as x-rays, CT, MRI and nuclear scans to diagnose VFs. 
    Vertebral fractures are common in older men and women, and are associated with increased mortality. Their occurrence can also predict future VFs and fractures at other sites, as well as chronic back pain and functional limitations. Knowledge of their presence can change the management of a patient.
    VFA has the advantage of less radiation, lower cost, convenience (at time of BMD) and comparable sensitivity and specificity to spine x-rays. Medical evidence and modeling suggests that patients with “low bone mass” with a VF who receive medical therapy show a significant risk reduction in fractures. While CT and spine radiographs have superior resolution to VFA, they are more expensive and involve higher radiation than VFA. MRI has good resolution and is useful to determine anatomy (eg. if kyphoplasy contemplated), to evaluate for other disorders such as malignancy, and to help determine the age of the fracture. VFA offers the advantage that it can be obtained at the time of DXA.

The authors conclude that the following are indications for VFA:

The authors conclude that VFA is a useful adjunct to BMD testing, particularly when results may influence clinical decision-making. Risk stratification of patients at risk of fracture, who otherwise might not be considered for pharmacologic therapy, is an important benefit of this technology.

 

Elder GJ, Mackun K.   25-Hydroxyvitamin D deficiency and diabetes predict reduced BMD in patients with chronic kidney disease. J Bone Miner Res. 2006 Nov;21(11):1778-84.
Bone disease is very prevalent in chronic kidney disease (CKD), as low levels of 1,25 dihydroxyvitamin D in this population contribute to abnormal mineralization and bone turnover.  Thus, active forms of vitamin D (calcitriol and analogues) are commonly used to treat these patients.  Low levels of 25-hydroxyvitamin D have also been demonstrated in pre-dialysis as well as dialysis patients, and can be associated with osteomalacia.  However, the role of treatment with vitamin D is unclear since renal 1-alpha hydroxylase activity, required to convert 25-hydroxy- to 1,25- dihydroxyvitamin D, is significantly reduced in CKD.  In the general adult population, levels of 25-hydroxyvitamin D are positively associated with bone mineral density (BMD), but there are few data regarding its association with BMD and fracture in a CKD population. The authors present a study of 242 primarily Caucasian patients (mean age 43 years; 61% men) with Stage 5 CKD, 35% secondary to DM (primarily type 1).  Most were on peritoneal dialysis (PD, 23%) or hemodialysis (HD, 62%), and 15% had not yet started dialysis.  Vitamin D levels were measured throughout the year, 50% in Spring/Summer and 50% Winter/Fall.  

Results: The serum 25-hydroxyvitamin D level for the total group was 67+ 34 nM, which meets the criteria for D insufficiency (see Table below). Vitamin D deficiency was present in 28% in the DM group, and in 12 % of the remainder of the group (p < 0.0001). Overall, patients on HD had higher levels than those on PD or pre-dialysis (HD; 77 +/- 34 nM versus 49 +/- 26; p < 0.0001) and women had lower levels than men (51 +/- 25 versus 77 +/- 35 nM; p < 0.0001).  Mean 1,25 dihydroxyvitamin D levels were in the low normal range (nl range, 26-120 pM), and higher in subjects on calcitriol than those not on supplementation.  When BMD Z scores were evaluated, the group overall had normal values.  However, 25-hydroxyvitamin D levels correlated positively to BMD, and hip BMD was inversely related to prevalent fracture. Those with DM had significantly lower Z scores at all sites.  Patients with parathyroidectomy (12%) had higher BMD Z scores; in nonparathyroidectomy patients Z scores were inversely related to intact PTH levels.  There was and inverse relationship between Z scores (all sites) and alkaline phosphatase suggesting that high bone turnover has a negative effect on BMD in patients with CKD, and that parathyroidectomy may reverse some of these negative effects.

The current study is limited by its cross-sectional design, but does suggest that 25-hydroxyvitamin D may be an important factor in bone health in the CKD population. Measurement and supplementation of 25-hydroxyvitamin D levels may be a practical consideration in this population.  Randomized, controlled trials are needed to assess the benefit of Vitamin D therapy in a CKD population.   

Vitamin D definitions (performed by Diasorin assay)
Deficiency: < 15 ng/ml (< 37 nM)
Insufficiency: 15-30 ng/ml (37- 75 nM)
Normal: 30-53 ng/ml (75-131 nM)

Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years.  Bonnick S, Saag KG, Kiel DP, McClung M, Hochberg M, Burnett SA, Sebba A, Kagan R, Chen E, Thompson DE, de Papp AE. J Clin Endocrinol Metab. 2006 Jul;91(7):2631-7.
A 2-year randomized, double-blind multi-center trial (extension of the original FACT trial) is presented to compare changes in bone mineral density (BMD), markers of bone turnover and gastrointestinal side effects of weekly treatment with alendronate (ALN) 70 mg versus risedronate (RIS) 35 mg/week.  Subjects were postmenopausal women (N= 1053 women randomized) with BMD less than 2 standard deviations below young adult mean at one or more of four sites (spine, total hip, trochanter or femoral neck). BMD was measured by DXA at baseline, 6, 12 and 24-months, and markers of bone resorption (urine NTX, serum CTX) and formation (BSAP, P1NP) were measured at baseline 3, 6, 12 and 24-months.  Women with 25-hydroxyvitamin D levels < 10 ng/ml were excluded.
At baseline, mean age was 64 years and women were on average 18 years post menopause.  Baseline T-scores for L-spine were – 2.3, and for total hip and femoral neck -1.8 and -2.1 SD.  After 24- months, BMD increased significantly in both the ALN and RIS groups compared with baseline values, with greater increases in the ALN group at all sites: L-spine 5.2% versus 3,4%; femoral neck 2.8% compared with 1.0%; total hip 3.0% compared with 1.3%; and trochanter 4.6% compared with 2.5% (ALN versus RIS, respectively). The % differences in mean BMD measurements increased over time between the two treatments favoring greater changes in the ALN group.  At 24-months there was a 1.8% difference at the L-spine; a 1.9% at the femoral neck and 1.7% at the total hip.    Biochemical markers of bone turnover including bone resorption and bone formation were significantly reduced in both groups during the study; however, the subjects on alendronate had greater decreases than the risedronate group.
Overall, the gastrointestinal side effects were similar for both treatment groups, 24.8% for ALN and 22.9% for RIS.  Dyspepsia, nausea and reflux disease were the most commonly reported adverse effects. 
Although this study demonstrates greater BMD improvement and turnover reduction with ALN 70 mg/week compared with RIS 35 mg/week, the results need to be interpreted with caution.  The study was not powered to answer the most relevant question- whether there are fewer fractures in subjects using one drug compared with the other.  Thus, the differences shown between these two antiresorptives cannot be interpreted to necessarily apply to the most relevant issue, fracture reduction. 

Testosterone Use in Men and Its Effects on Bone Health. A Systemic Review and Meta-Analysis of Randomized Placebo-Controlled Trials. Trasz MJ, Kostandinos S, Bolona ER et al. JCEM 91 (6) : 2011-2016.   (July 2006)
Hypogonadal men are at risk for bone loss and osteoporosis and possibly fractures.  In this review/meta-analysis the authors evaluate the use of testosterone (T) replacement to enhance bone mass and decrease fractures in hypogonadal men at risk.  The authors evaluated randomized-controlled trials that included any men with any degree of androgen deficiency. They determined the effect size and 95% confidence interval for the difference between arms (T vs placebo) in L-spine and Femoral Neck BMD.  Ten studies were included in the meta-analysis of bone health; however, 2 were excluded because of lack of reported data on BMD. 
The analysis showed a small but significant increase in L-spine BMD with T replacement (effect size 0.31) corresponding to a 4% increase in L-spine BMD.  They also found a small but non-significant increase in F Neck BMD of 45.  In sub-group analyses, 3 trials enrolled patients on glucocorticoids.  The analysis showed the effect of T on L-spine was consistent across these trials and 9% increased, but the effect size on Femoral Neck BMD was not significant and inconsistent across studies.  Two studies enrolled men with low mean T levels, but this analysis showed no treatment-baseline T level interaction.  In terms of route of administration, intramuscular T showed a significant and moderate effect size on L-spine BMD increase (8%) as compared with the pooled estimate from studies using transdermal T.  There was no route- treatment interaction at the Femoral Neck.
In conclusion, the available data suggest a role for T in improving skeletal health, particularly at the L-spine, in men with mild hypogonadism.  Those with profound hypogonadism were underrepresented in the present analysis.  In addition, no data are given re side effects of T treatment..  Finally, larger randomized controlled trials to determine fracture efficacy are not available at the current time. 

 

 

Effects of Oral Alendronate on BMD in Adult Patients With Osteogenesis Imperfecta 16 Feb 2006
Chevrel G, Schott AM, Fontanges E, Charrin JE, Lina-Granade G, Duboeuf F, Garnero P, Arlot M, Raynal C, Meunier PJ.  Effects of Oral Alendronate on BMD in Adult Patients With Osteogenesis Imperfecta: A 3-Year Randomized Placebo-Controlled Trial.
J Bone Miner Res. 2006 Feb;21(2):300-6.
This 3-year randomized double-blind, placebo-controlled trial determined the effect of daily oral alendronate 10 mg versus placebo on bone density in adults with osteogenesis imperfecta (OI).  Two other studies of adults with OI, using intravenous bisphosphonates, have been done previously; however, they were open studies and not randomized controlled trials.
    Sixty-four patients were randomized, and they all met the criteria for OI and had a low BMD of either the lumbar spine or hip.  BMD was measured annually.  Subjects received 10 mg daily oral alendronate or a matching placebo.  Elemental calcium 1000 mg and 800 IU vitamin D3 was given to all subjects.  At baseline 33 subjects were randomized to placebo and 31 were randomized to alendronate.  The mean age in each group was 37 and 36 years, respectively.  All baseline characteristics were similar for the two groups with the exception of serum 25-OH vitamin D which was slightly lower in the placebo group.
    Lumbar spine BMD was the same at baseline in both groups.  At 36 months, BMD was significantly higher in the alendronate group, with a 9.4 + 2.0% difference between the groups.  The BMD in the placebo group did not change during the 36 months of the study.  In the alendronate group, spine BMD increased by 10% over baseline after 36 months, with a 7.5% increase in the first year (p<.001).  BMD at the femur increased by 3.3% over the study period, and the placebo group decreased slightly. The increase in the alendronate treated group was significantly greater than the placebo group.
    Biochemical markers of bone turnover, including both formation and resorption markers, significantly decreased in the alendronate group, but no changes were observed in the placebo group.  The incidence of fractures, vertebral or peripheral, was not significantly different between the groups.  In addition, there were no hearing changes in either group and pain scores were similar in both groups.  While there were no significant differences in overall incidence of adverse events, gastrointestinal adverse effects were more frequently observed in the alendronate group. 
    In conclusion, oral alendronate appears to be a good alternative to intravenous bisphosphonates in adult patients with OI.  Whether an increase in BMD seen with alendronate treatment is associated with lower fracture rates is not clear, as this study was not powered to answer that question, and a larger trial would be required to address that issue.

16 Nov 2005 -(PAGET'S DISEASE)-Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease.
Reid IR, Miller P, Lyles K, Fraser W, Brown JP, Saidi Y, Mesenbrink P, Su G, Pak J, Zelenakas K, Luchi M, Richardson P, Hosking D. N Engl J Med. 2005 Sep 1;353(9):898-908
            These authors describe the results of two identical, randomized, double-blind, actively controlled trials of 6 months' duration, where one 5mg infusion of zoledronic acid versus placebo was compared with 60 days of oral risedronate (30 mg per day) for the treatment of Paget’s disease.  The two trials included patients from North America, Europe, Australia and South Africa: 182 patients were randomized to zoledronic acid or placebo; 175 subjects were randomized to risedronate or placebo.  All subjects received 1 gram of calcium per day, and 400-1000 IU of calciferol per day.    The main outcome measures were rates of therapeutic response at 6-months defined as normalization of alkaline phosphatase levels or a reduction of at least 75 percent in the total alkaline phosphatase excess. The results of the two studies were pooled.
           At six months, 96.0 percent of patients receiving zoledronic acid had a therapeutic response (169 of 176), as compared with 74.3 percent of patients receiving risedronate (127 of 171, P<0.001). Alkaline phosphatase levels normalized in 89 percent of patients in the zoledronic acid group and 58 percent of patients in the risedronate group (P<0.001). Zoledronic acid was associated with a shorter median time to a first therapeutic response (64 vs. 89 days, P<0.001). Other markers of bone turnover including formation and resorption showed greater reductions in the zoledronic group compared with the risedronate group.
            Overall, the number of adverse events (serious or non-serious) was similar in both the zoledronic acid and risedronate group.  However, there were twice as many AEs in the first 3-days in the zoledronic group as there were in the risedronate group. These were primarily influenza-type symptoms that commonly occur with nitrogen-containing bisphosphonates.  Subsequently, rates of AEs were similar for the two groups including gastrointestinal and renal disorders.  *of note, hypocalcemia does occur more often in the zoledronic acid group; two patients were symptomatic.  One subject in the risedronate group became hypocalcemic requiring hospitalization. 
            A quality of life measure survey showed a significant increase from baseline at both three and six months in the zoledronic acid group and differed significantly from those in the risedronate group at three months. Pain scores improved in both groups.
            In conclusion, a single infusion of zoledronic acid produced a more rapid and more sustained response in Paget's disease than did daily treatment with risedronate.  This therapy could potentially translate into a more convenient and longer duration of response for patients with Paget’s disease. 

1 Oct 2005--(OSTEOPOROSIS)-- Black DM, Bilezikian JP, Ensrud KE, Greenspan SL, Palermo L, Hue T, Lang TF, McGowan JA, Rosen CJ; PaTH Study Investigators. One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med. 2005 Aug 11;353(6):555-65.<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16093464&query_hl=1>
     The PaTH (Parathyroid Hormone and Alendronate Study) study was designed to determine whether it is essential to follow 1-year of parathyroid hormone (PTH) therapy with an antiresorptive drug to maintain gains in bone density.  Women were randomly assigned to one of four groups: PTH 100 ug/d in year 1 followed by placebo in year 2 (N=60); PTH 100 ug/d in year 1 followed by weekly alendronate in year 2 (N=59); PTH plus alendronate in year 1 followed by alendronate in year 2 (N=59); alendronate in years years 1 and year 2. 
     From prior studies, both classes of agents are effective as monotherapy. However, the combination of PTH with a bisphosphonate increases bone mass to a lesser extent that PTH alone.  If no therapy is given after PTH (PTH-placebo), then the gains are lost over the following year. Bisphosphonates in the year following treatment with PTH appear to conserve the gains in BMD obtained by therapy with PTH during the first year.  This study has important implications for clinical practice, suggesting that optimal therapy is with PTH alone, followed by a bisphosphonate.

 6 Oct 2005 --(OSTEOPOROSIS)  Cosman   F, Nieves J, Zion M, Woelfert L, Luckey M, Lindsay R.
Daily and cyclic parathyroid hormone in women receiving alendronate.
N Engl J Med. 2005 Aug 11;353(6):566-75.<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16093465&query_hl=2>
One-hundred and twenty-six women who  received alendronate therapy for at least one year (mean of 3-years) were continued on alendronate and were randomly assigned to receive either daily injections of synthetic parathyroid hormone (25ug/day) subcutaneously, alternating 3-month cycles of PTH (3-months “on” with 3-months “off”) or continued weekly alendronate for 15 months.  In both PTH groups bone formation increased significantly, however, in the women on cyclic treatment bone formation decreased during the “off” cycle.  Bone resorption increased in both PTH groups, but more so in the daily than the cyclic group.  Bone density gains in the spine were similar in the two PTH groups, and on the order of 5-6%, while in the alendronate only group BMD remained stable. Adherence was excellent in all groups, however, there were more musculoskeletal symptoms and elevated urinary calcium:creatinine ratios in the daily PTH group.  This study suggests that cyclic PTH may be sufficient to produce bone density effects similar to daily PTH and at a lower cost and easier effort for patients, although parameters of bone strength and microarchitecture which PTH produces were not investigated in this study.