'Give me something meaningful': GPs perspectives on how to improve an audit and feedback report provided by health insurers - an exploratory qualitative study.

BACKGROUND: Audit and feedback (A&F) is a valuable quality improvement strategy, which can contribute to de-implementation of low-value care. In the Netherlands, all health insurers collaboratively provide A&F to general practitioners (GPs), the 'Primary Care Practice Report' (PCPR). Unfortunately, the use of this report by GPs is limited. This study examined the thoughts of GPs on the usability of the PCPR and GPs recommendations for improving the PCPR. METHOD: We used an interpretative qualitative design, with think-aloud tasks to uncover thoughts of GPs on the usability of the PCPR and semistructured interview questions to ask GPs' recommendations for improvement of the PCPR. Interviews were audiorecorded and transcribed ad verbatim. Data were analysed using thematic content analysis. RESULTS: We identified two main themes: 'poor usability of the PCPR', and 'minimal motivation to change based on the PCPR'. The GPs found the usability of the PCPR poor due to the feedback not being clinically meaningful, the data not being recent, individual and reliable, the performance comparators offer insufficient guidance to assess clinical performance, the results are not discussed with peers and the definitions and visuals are unclear. The GPs recommended improving these issues. The GPs motivation to change based on the PCPR was minimal. CONCLUSIONS: The GPs evaluated the PCPR as poorly usable and were minimally motivated to change. The PCPR seems developed from the perspective of the reports' commissioners, health insurers, and does not meet known criteria for effective A&F design and user-centred design. Importantly, the GPs did state that well-designed feedback could contribute to their motivation to improve clinical performance.Furthermore, the GPs stated that they receive a multitude of A&F reports, which they hardly use. Thus, we see a need for policy makers to invest in less, but more usable A&F reports.

Pharmacokinetic and pharmacodynamic evaluation of the novel CCR1 antagonist CCX354 in healthy human subjects: implications for selection of clinical dose.

The safety and pharmacokinetic (PK)/pharmacodynamic (PD) profile of the novel CCR1 antagonist CCX354 was evaluated in double-blind, placebo-controlled, single- and multiple-dose phase I studies (1-300 mg/day oral doses). CCX354 was well tolerated and displayed a linear dose-exposure profile, with half-life approaching 7 h at the 300-mg dose. The extent of CCR1 receptor blockade on blood monocytes, which correlated well with plasma concentrations of the drug, was assessed using fluorescently labeled CCL3 binding in whole blood from phase I subjects. High levels of receptor coverage at the 12-h time point were achieved after a single dose of 100 mg CCX354. Preclinical studies indicate that effective blockade of inflammatory cell infiltration into tissues requires ≥90% CCR1 inhibition on blood leukocytes at all times. The comparison of the properties of CCX354 with those published for other CCR1 antagonists has informed the dose selection for ongoing clinical development of CCX354 in rheumatoid arthritis (RA).

Canine hip extension range during gait.

Assessment of canine gait is frequently used by veterinary clinicians to establish the presence of orthopaedic pain. As up to 30% of canine orthopaedic conditions affect the pelvic limb, knowledge of pelvic limb biomechanics during gait is very important. Previous studies have investigated the biomechanics at the tarsus and stifle, but little information is available regarding hip motion during gait. The aim of this study was to determine the maximum hip extension range achieved during the stance phase of gait in normal canines. In addition, this study aimed to determine the difference between maximum passive hip extension and maximum hip extension during gait. Using a sample of 30 morphologically similar normal dogs, mean maximum passive hip extension was measured using a goniometer and mean maximum hip extension range during gait was determined videographically. Inter- and intra-assessor reliability studies performed at the start of the study showed that the measurement tools and techniques used in this study were valid and reliable. The goniometric data showed that mean maximum passive hip extension range was 162.44 degrees (+/-3.94) with no significant difference between the left and the right hind limbs. The videographic data showed that mean maximum hip extension range during gait was 119.9 degrees (+/-9.26) with no significant difference between the left and right hind limbs. The results of this study provided reference values for active and passive hip extension range and showed that the degree of hip extension range required for normal gait is significantly less than maximum passive hip extension range.

The heart remembers: observations of cardiac memory in the Dorper sheep heart.

Memory is a property common to a diverse range of tissues. Cardiac memory has been demonstrated in the human, dog, rat and rabbit. This is a peculiar phenomenon, reflected in the T wave of the electrocardiogram. The heart is able to remember periods of alterations in the sequence of ventricular activation and once there is a return to a normal sequence of ventricular activation the T waves may manifest memory. Cardiac memory is noted when the T wave during normal ventricular activation retains the vector of the previous abnormal QRS complex, caused by a period of altered ventricular activation. Possible mechanisms of memory in the heart are alterations of the transient outward potassium current (I10) in ventricular myocytes and new protein synthesis inside myocytes. These two mechanisms operate in short- and long-term cardiac memory respectively. Currently, it is unknown whether memory may have adverse structural consequences in the heart. We were able to demonstrate memory in the hearts of Dorper wethers and this is the first report of cardiac memory in Dorper sheep.

The effect of a single dose of osteoprotegerin in postmenopausal women.

Osteoprotegerin (OPG), a tumor necrosis factor (TNF) receptor family member, is a critical regulator of bone resorption. It is an important inhibitor of the terminal differentiation and activation of osteoclasts. This randomized, double-blind, placebo-controlled, sequential dose escalation study was conducted in postmenopausal women to determine the effect of a single subcutaneous (s.c.) dose of OPG on bone resorption as indicated by the biochemical markers, urinary N-telopeptide (NTX) and deoxypyridinoline (DPD), which are stable collagen degradation products. NTX levels decreased within 12 h after OPG administration. At the highest dose administered (3.0 mg/kg), a mean percent decrease in NTX of approximately 80% was observed 4 days after dosing. Six weeks after dosing a mean decrease of 14% in NTX was observed. The levels of bone-specific alkaline phosphatase (BSAP), a marker of bone formation, did not change for approximately 3 weeks after dosing. Thereafter, a modest decrease, reaching approximately 30% at 6 weeks, was observed in the 3.0-mg/kg dose group. The rapid decrease from baseline in NTX and delayed decrease in BSAP indicated that OPG acted primarily on osteoclasts to decrease bone resorption. OPG injections are well tolerated. This study, for the first time, indicates that a single s.c. injection of OPG is effective in rapidly and profoundly reducing bone turnover for a sustained period and that OPG therefore may be effective in treatment of bone diseases characterized by increased bone resorption such as osteoporosis.

Esophageal transit of risedronate cellulose-coated tablet and gelatin capsule formulations.

Risedronate sodium is an orally active antiresorptive agent and a member of the pyridinyl class of bisphosphonates. It has been approved for the treatment of Paget's disease of the bone and is under development as a chronic therapy for the treatment and prevention of osteoporosis. A novel cellulose film-coated tablet formulation was developed to optimize esophageal transit of this bisphosphonate. The aim of the present study was to compare the esophageal transit of the film-coated tablet formulation of risedronate with its original gelatin capsule dose form. A total of 25 elderly, healthy volunteers (mean 66 years), who were dysphagia-free, participated in this randomized cross-over study. On separate occasions, volunteers swallowed radiolabeled placebo formulations with 50 ml water. Dynamic images with participants in a sitting position were recorded for 10 min using a gamma camera. Scintigraphic imaging showed a delay in esophageal transit (greater than 15 s) in 28% of patients in the capsule group but in none of the tablet group (P<0.05). The mean transit times of the capsules and tablets were 23.8 and 3.3 s, respectively. Esophageal transit of film-coated tablets was faster than gelatin capsules, suggesting that film-coated tablets would be the appropriate formulation for all pivotal trials with risedronate and for subsequent commercialization.

A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget's disease of bone. Paget's Risedronate/Etidronate Study Group.

PURPOSE: To compare the efficacy and tolerability of oral risedronate and etidronate for treatment of Paget's disease of bone. PATIENTS AND METHODS: Patients from 12 centers in North America received risedronate 30 mg daily for 2 months (62 patients) or etidronate 400 mg daily for 6 months (61 patients) in a prospective, randomized, double-blind study. Serum alkaline phosphatase (the primary variable), serum bone-specific alkaline phosphatase, and urinary deoxypyridinoline concentrations were monitored for 12 to 18 months. RESULTS: Serum alkaline phosphatase concentration normalized by month 12 in 73% of risedronate-treated patients, compared with 15% of those receiving etidronate (P <0.001). Median time to normalization was 91 days for risedronate-treated patients and >360 days for etidronate-treated patients (P <0.001); relapse rates were 3% in the risedronate group and 15% in the etidronate group (P <0.05). At month 18, 53% of the risedronate group and 14% of the etidronate group remained in biochemical remission. Urinary deoxypyridinoline normalized in 87% of patients on risedronate and 57% of patients receiving etidronate (P <0.01); serum bone-specific alkaline phosphatase normalized in 73% of patients on risedronate and 18% of patients on etidronate (P <0.001). Patients who had received etidronate previously had a blunted response to etidronate, but not to risedronate. Reductions in pain were statistically significant in the risedronate group, but not in the etidronate group. Both drugs were well tolerated. CONCLUSION: Although etidronate is effective, risedronate offers a shorter duration of therapy, better and longer-lasting remission, significant reductions in pain, and provides additional remission in subjects who exhibited an incomplete response to previous etidronate treatment.

Risedronate, a highly effective, short-term oral treatment for Paget's disease: a dose-response study.

Risedronate is a potent pyridinyl bisphosphonate being developed for bone diseases such as Paget's disease and osteoporosis. In this study, we compared the efficacy, safety, and tolerability of three different doses of oral risedronate in 62 patients with severe Paget's disease of bone [serum alkaline phosphatase (AP) >3 times the upper limit of normal]. Patients were treated at six study centers with either 10, 20, or 30 mg oral risedronate daily for 28 days and followed up to day 85. The primary efficacy parameter was percentage change from baseline in AP excess. The data show that there is a dose-response with risedronate: patients who received 30 mg oral risedronate for 28 days benefited most, with a mean percentage decrease in AP excess of 72.2% (20 mg: 57.9%; 10 mg: 48. 0%). Time to response-the first time point when there was a >/=30% reduction from baseline in AP excess and >/=50% reduction from baseline in urinary hydroxyproline (HP)/creatinine-was also significantly shorter (median 29 days) in the 30 mg group compared with the other two groups (20 mg: 43 days and 10 mg: 71 days). Long-term follow-up data up to 33 months from the start of the study indicated that AP remained below baseline levels for all patients. Histologic evaluation of bone formed during risedronate therapy demonstrated that normal lamellar bone was formed as opposed to woven pagetic bone, with no evidence of osteomalacia. Risedronate was well tolerated. Transient decreases in serum calcium and increases in serum intact parathyroid hormone were observed, consistent with the pharmacology of risedronate. In conclusion, risedronate administered at daily doses of 10, 20, and 30 mg for 28 days was effective in reducing the biochemical indices of disease activity in patients with severe Paget's disease of bone. A daily dose of 30 mg was most effective without compromising safety or tolerability.

Lung cancer, tobacco, and environmental factors in the African population of the Northern Province, South Africa.

DESIGN: Case-control study among incident African patients with cancer. Questionnaire assessment of exposure to tobacco, occupation, and place of birth. SETTING: Northern Province, South Africa. SUBJECTS: Between 1993 and 1995, 288 men and 60 women with lung cancer and 183 male and 197 female controls (consisting of patients newly diagnosed with cancers other than those known to be associated with smoking) were interviewed. Unmatched, unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) of developing lung cancer in relation to a number of variables. MAIN OUTCOME MEASURE: Risk of developing lung cancer related to exposure to tobacco, indoor pollution, dusty work environment, and residential exposure to asbestos. RESULTS: There was a significant increase in the risk of developing lung cancer through smoking. In men, the ORs were 2.2 (95% CI = 1.0 to 4. 6) in ex-smokers, 9.8 (95% CI = 5.9 to 16.4) in light smokers (0-14 g/day), and 12.0 (95% CI = 6.5 to 22.3) in heavy smokers. In women, the ORs were 5.8 (95% CI = 1.3 to 25.8) in ex-smokers and 5.5 (95% CI = 2.6 to 11.3) in current smokers. Work in a dusty industry showed an elevated risk (OR = 3.2, 95% CI = 1.8 to 5.8) for lung cancer only in men. Male residents of areas where asbestos was shipped for distribution (termed moderately polluted asbestos areas) had a 2.5-fold increase (95% CI = 1.0 to 4.4) in the risk (OR) of developing lung cancer, and residents of areas where asbestos was mined (termed heavily polluted asbestos areas) had a 2.8-fold increase in risk (95% CI = 0.7 to 10.4). Female residents of heavily polluted asbestos areas showed elevated risks of 5.4 (95% CI = 1.3 to 22.5) of developing lung cancer. CONCLUSION: The data suggest that tobacco smoking is the most important risk factor for the development of lung cancer in this setting. Risks for lung cancer are reminiscent of those observed in Western countries in the 1960s and 1970s. However, environmental exposure to asbestos, a dusty occupation (in men), and perhaps indoor air pollution may also contribute to the development of lung cancer in this province.

Risedronate, a highly effective oral agent in the treatment of patients with severe Paget's disease.

Thirteen patients with severe Paget's disease of bone [mean serum alkaline phosphatase (SAP) level 17 times the upper limit of normal] were treated with 30 mg oral risedronate daily for 8 weeks. Patients were followed for 16 weeks without treatment. The change from baseline SAP was the primary end point. Those patients whose SAP levels did not reach the normal range were retreated with 30 mg for another 8 weeks. There was a mean percent decrease in SAP of 77% after the first course of risedronate treatment and 87% after the second course of treatment. All patients who completed the study had a decrease in SAP of at least 77% from the baseline. The urinary hydroxyproline/creatinine level was decreased by 64% and 79%, respectively, during the first and second treatment courses. There were transient asymptomatic decreases in serum calcium and phosphorus levels. The urinary calcium/creatinine ratio also decreased in these patients. Serum intact PTH and 1,25-dihydroxyvitamin D levels increased transiently during risedronate treatment. Oral risedronate was well tolerated by the patients. Only one patient discontinued treatment because of an adverse event (diarrhea) thought to be related to risedronate therapy.

Risedronate in the treatment of Paget's disease of bone: an open label, multicenter study.

An open-label, multicenter study was conducted to determine the efficacy and safety of oral risedronate (a pyridinyl bisphosphonate) in 162 patients (102 men, 60 postmenopausal women; mean age, 68 years) with moderate to severe Paget's disease of bone (mean serum alkaline phosphatase [ALP] approximately seven times the upper limit of normal). Patients were treated with oral risedronate, 30 mg/day for 84 days, followed by 112 days without treatment. This 196-day cycle was repeated once if serum ALP did not normalize or increased from the nadir value by > or = 25%. At the end of the first and second cycles, the mean percentage decreases for serum ALP were 65.7% and 69.1%, and for urinary hydroxyproline/creatinine 50.4% and 66.9%, respectively. The decreases from baseline in ALP and urinary hydroxyproline/creatinine were significant (p < 0.001). Normalization of serum ALP was observed in 86 patients (53.8%): 53 during the first treatment cycle and 33 during the second. There was a significant proportion of patients reporting a decrease in the pagetic bone pain at days 84 and 196 (p < 0.001). Overall, risedronate was well tolerated. Five patients withdrew due to adverse events, none of which were considered to be drug related. In conclusion, 30 mg of oral risedronate administered daily for 84 days significantly reduced the biochemical indices of disease activity and was associated with pain reduction in patients with moderate to severe Paget's disease of bone. Normalization of ALP was observed in the majority of patients. Repeated administration of risedronate was shown to be beneficial. In general, risedronate was well tolerated and demonstrated a good safety profile.

Risedronate gastrointestinal absorption is independent of site and rate of administration.

PURPOSE: Two studies were conducted to compare the absorption of risedronate administered as a solution to three different gastrointestinal sites (study A) and to determine the extent of absorption of risedronate solution administered by rapid and slow infusion to the second part of the duodenum (study B). METHODS: Each study was designed as a single-dose, crossover (three periods, study A; two periods, study B) trial in healthy male subjects, with a 14-day washout period between dosing. Subjects fasted overnight before drug administration and for 4 hours after drug administration. In study A, a risedronate solution of 40 mg in 30 mL of water was administered directly into the stomach, the second part of the duodenum, or the terminal ileum over 1 minute via a nasoenteral tube in a three-period crossover design. In study B, a risedronate solution of 40 mg in 30 mL of water was administered directly into the second part of the duodenum over 1 minute and over 1 hour in a randomized, two-period crossover design. Serum and urine samples were obtained for 48 hours after dosing for risedronate analysis. RESULTS: Eight subjects completed each study. No statistically significant site-specific differences in any pharmacokinetic parameter were observed (study A). Based on the area under the serum concentration-time profile and the amount of drug excreted in the urine unchanged, the extent of risedronate absorption did not differ significantly following a rapid or a slow infusion (study B). Only minor symptomatic complaints were reported by subjects, such as headaches and body aches. CONCLUSIONS: These studies indicate that the rate and extent of risedronate absorption are independent of the site of administration along the gastrointestinal tract, and that the extent of absorption is not affected by the rate of administration.

Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow-up.

This double-blind, placebo-controlled study was undertaken to determine 1) the efficacy of oral risedronate for prevention of bone loss in healthy, early postmenopausal patients with normal bone mass, 2) the effect on bone mass when treatment was stopped, and 3) the safety and tolerance of risedronate in this population. A group of 111 patients were randomized to oral placebo, risedronate 5 mg daily, or risedronate 5 mg cyclically, for 2 yr followed by 1 yr off treatment. Measurements included percentage change from baseline in lumbar spine bone mineral density (BMD) at 24 months; percentage change from baseline in BMD of the femoral neck, trochanteric region, and Ward's triangle region of the proximal femur; and changes in biochemical markers of bone turnover. After 2 yr, there was a mean increase in BMD of the lumbar spine of 1.4% from baseline and of 5.7% vs. placebo in the risedronate 5 mg daily group. There were decreases from baseline in BMD of 1.6% and 4.3% in the risedronate 5 mg cyclic and placebo groups, respectively. By the end of 24 months, trochanteric bone mass at the hip increased by 5.4% in the risedronate 5 mg daily group and by 3.3% in the risedronate 5 mg cyclic group vs. placebo. Bone mass was maintained at the femoral neck in the 2 active-treatment groups vs. a 2.4% mean loss with placebo. During the treatment-free follow-up, bone turnover increased toward baseline in both risedronate groups. By the end of that year, lumbar spine bone mass in all 3 groups was lower than at baseline. Oral risedronate was well tolerated. We conclude that risedronate (5 mg daily) increases bone mass and risedronate (5 mg cyclic) appears to prevent bone loss in early postmenopausal women with normal BMD.

Impaired oesophageal transit of capsule versus tablet formulations in the elderly.

Drug induced oesophageal injury is an important and preventable cause of iatrogenic injury. In most cases the injury is considered to be due to mucosal contact from formulations lodged in the oesophagus. A scintigraphic study was performed comparing the oesophageal transit of enteric coated tablets with similar sized and shaped gelatin capsules, using a population of elderly healthy volunteers similar in age (50-79 years) to the population most likely to be receiving regular treatment. Twenty three volunteers injected the radiolabelled tablet or capsule with 50 ml of water while sitting on two separate occasions according to a randomisation schedule. Oesophageal transit was assessed by gamma scintigraphy. Gastric residence was also assessed in 11 of 23 subjects. While the tablet was readily cleared from the oesophagus, mean transit time 4.3 seconds (range 1.0-14.0), the capsule often showed a comparatively prolonged holdup, mean transit time 20.9 seconds (range 1.5-174.5). Ten of 11 tablets emptied from the stomach intact, while all 11 capsules broke up in the stomach. Gelatin capsules showed a clear tendency to remain within the oesophagus of healthy elderly volunteers, while similar sized enteric coated tablets did not. These studies show the importance of assessing oesophageal transit when designing the formulation of drugs with a potential for oesophageal injury.

Effect of estrogen on acidification in osteoclasts.

Isolated chicken osteoclasts were neutralized with NH4Cl, then recovery of acid formation was monitored by measuring acridine orange fluorescence over a period of 4 hrs. Estradiol-17 beta and diethylstilbestrol (DES), in nanomolar amounts, blocked acidification 20% to 60%. Effects were detectable in 30 min and maximal by one hr. Estradiol-17 alpha was ineffective. This action of estradiol is believed to be mediated at the plasma membrane since the response was rapid and was not affected by cycloheximide inhibition of protein synthesis. Stimulation of acidification by PTH and cyclic AMP was blocked by estradiol. Estradiol was inhibitory to the same extent as calcitonin; these effects were not additive. Estradiol-17 beta and DES, in micromolar but not in nanomolar amounts, blocked proton pumping in isolated plasma membrane vesicles.

Demonstration of calmodulin-sensitive calcium translocation by isolated osteoclast plasma membrane vesicles.

Plasma membrane vesicles were prepared from chicken osteoclasts, and active calcium transport was demonstrated in a spectrofluorimetric assay using the fluorescent calcium concentration indicator, fura-2. Transport activity was inhibited by quercetin (10 microM), sodium vanadate (10 microM), and the anticalmodulin agents, compound 48/80 (20 and 200 micrograms/ml) and calmidazolium (10 and 20 microM). The transport rate (Vmax, 1.3 nmol/mg protein/min) was not altered in the presence of the protonophore, nigericin (1 microM), indicating that proton transport was not driving calcium transport. Release of accumulated calcium in the vesicles occurred with the addition of bromo-A23187 (5 microM) or ionomycin (5 microM). Increasing calcium transport occurred with increasing calcium concentration. Finally, the calmodulin content of the vesicles was demonstrated to be 54-134 U/mg protein. These results demonstrate that a calmodulin-sensitive, ATP-dependent calcium transporter is present in the osteoclast plasma membrane.

Characterization of the functional stages of osteoclasts by enzyme histochemistry and electron microscopy.

To investigate the functional stages of osteoclasts, the ultrastructural histochemical distribution of the lysosomal enzymes [acid phosphatase (tartrate-sensitive) and neutral phosphatase], the plasma membrane enzymes [alkaline phosphatase, Ca(++)-ATPase, and alkaline ouabain-insensitive p-nitrophenylphosphatase (alkaline p-NPPase)], and the mitochondrial enzyme (cytochrome C oxidase) was evaluated in the chicken tibial metaphysis. Both active-appearing and detached (resting) osteoclasts were studied. Serial sectioning was used to identify detached osteoclasts which were present in the perivascular space. The ultrastructure of detached osteoclasts was similar to that of active osteoclasts, except for the lack of a ruffled border and clear zone, and an altered distribution pattern of small vesicles. Small vesicles were uniformly distributed in the cytoplasm of resting osteoclasts, whereas they were concentrated beneath the ruffled border of active osteoclasts. Alkaline p-NPPase, a marker enzyme for the basal ruffled border, was also apparent on the membrane of small vesicles. However, the vesicles did not possess Ca(++)-ATPase, a marker enzyme for the apical plasma membrane. These findings support the concept that small vesicles serve as a membrane reservoir for the ruffled border membrane. Pre-osteoclasts contained abundant mitochondria and lysosomes, prominent Golgi complexes, moderately developed endoplasmic reticulum, and lacked small vesicles. Pre-osteoclasts appear to fuse with osteoclasts which are attached to the bone surface, but not with detached osteoclasts. The small vesicles, from which the ruffled border arises, are absent from pre-osteoclasts, suggesting that they develop after fusion with pre-existing osteoclasts or after attachment to the bone surface. Alkaline p-NPPase appears to be a marker for differentiation of pre-osteoclasts to mature osteoclasts.

Ultrastructural localization of tartrate-resistant acid phosphatase (purple acid phosphatase) activity in chicken cartilage and bone.

Tartrate-resistant acid adenosine triphosphatase activity at pH 6.5, using a lead-salt method, was localized at light and electron microscopic levels in cartilage and bone matrices, osteoclasts, and chondroclasts. Cartilage matrix staining occurred after vascular invasion of the growth plate. In osteoclasts, activity was present in lysosomes, extracellular ruffled border channels, and the underlying cartilage and bone matrices. Staining artifacts occurred at lower pH levels (pH 5.4, 5.0). Adenosine diphosphate, p-nitrophenylphosphate, thiamine pyrophosphate, and alpha-naphthylphosphate also acted as substrates; but no activity was observed when adenosine monophosphate, adenylate-(beta, gamma-methylene) diphosphate, and beta-glycerophosphate were used. The activity was inhibited by NaF, dithionite, and a high concentration of p-chloromercuribenzoic acid, and activated by simultaneous addition of FeCl2 and ascorbic acid, as has been shown in biochemical studies. These histochemical results support the view that the adenosine triphosphate hydrolyzing activity at pH 6.5 is due to tartrate-resistant acid phosphatase (TRAP). There were some differences in ultrastructural localization between TRAP and tartrate-sensitive acid phosphatase (TSAP) activities in osteoclasts: TSAP activity was more intense in lysosomes and Golgi complexes and TRAP was stronger in the cartilage and bone matrices. It is suggested, therefore, that most of TRAP is in an inactive form in cells and is activated when secreted.